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New FAAH inhibitors based on 3-carboxamido-5-aryl-isoxazole scaffold
that protect against experimental colitis
Virginie Andrzejaka, Giulio G. Mucciolib,e, Mathilde Body-Malapelc, Jamal El Bakalia, Madjid Djouinac,
Nicolas Renaultd, Philippe Chavatted, Pierre Desreumauxc, Didier M. Lamberte, Régis Milleta,⇑
aUniversité Lille Nord de France, ICPAL, EA 4481, IFR114, 3 rue du Professeur Laguesse, BP-83, F-59006 Lille, France
bUniversité Catholique de Louvain, Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids Lab, 72 Avenue E. Mounier (CHAM7230),
B-1200 Bruxelles, Belgium
cUniversité Lille Nord de France, INSERM U995, Faculté de Médecine, Amphi J & K, IFR114, Boulevard du Professeur Leclercq, F-59045 Lille, France
dUniversité Lille Nord de France, Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Chimie Thérapeutique, EA 4481, IFR 114, 3 rue du Professeur Laguesse,
BP-83, F-59006 Lille, France
eUniversité catholique de Louvain, Louvain Drug Research Institute, Unité de Chimie Pharmaceutique et de Radiopharmacie, 73 Avenue E. Mounier UCL (CMFA7340),
B-1200 Bruxelles, Belgium
a r t i c l ei n f o
Article history:
Received 10 February 2011
Revised 26 April 2011
Accepted 30 April 2011
Available online 6 May 2011
FAAH modeling
a b s t r a c t
Growing evidence suggests a role for the endocannabinoid (EC) system, in intestinal inflammation and
compounds inhibiting anandamide degradation offer a promising therapeutic option for the treatment
of inflammatory bowel diseases. In this paper, we report the first series of carboxamides derivatives pos-
sessing FAAH inhibitory activities. Among them, compound 39 displayed significant inhibitory FAAH
activity (IC50= 0.088 lM) and reduced colitis induced by intrarectal administration of TNBS.
? 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Endocannabinoids (ECs), including anandamide (AEA) and
2-arachidonoylglycerol (2-AG), are arachidonic acid derived bioac-
tive lipids that are biosynthesized on demand, and which, following
the activation of both cannabinoid receptors (CB1and CB2) trigger a
wide range of biological responses. These physiological effects are
transientdueto a rapidinactivation of ECsby specificenzymessuch
as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase
In the gastrointestinal tract, these endogenous ligands control,
notably via CB1and/or CB2receptor activation, many physiological
Accordingly, stimulation of cannabinoid receptors directly or
indirectly constitutes a promising strategy to treat several gastroin-
testinal pathologies, especially diseases wherein an inflammatory
process is involved such as, for example, inflammatory bowel
For that matter, increased levels of AEA as well as up-regula-
tion of cannabinoid receptors expression were reported during
intestinal inflammation,6–8and described as a protective mecha-
nism to counteract inflammation.9Over the past few years sev-
eral studies have provided evidence that exogenous agonists
acting at CB1 and/or CB2 receptors, as well as inhibitors of EC
re-uptake and degradation, provide protection against experimen-
tal colitis.10–12Indeed, it has been shown that the nonselective
cannabinoid receptor agonist HU210 as well as the two selective
CB2 receptor agonist JWH133 and AM1241 are able to signifi-
cantly reduce inflammation in hapten-induced colitis in mice.10
Consistent with these results, both genetic and pharmacological
blockade of either CB1or CB2receptor signaling led to a worsen-
ing of colitis in these experimental models.10Another approach
consisting in raising anandamide levels has been successfully ap-
plied to reduce intestinal inflammation by using inhibitors of EC
membrane transport (VDM11) or FAAH (URB597).11The involve-
ment of both cannabinoid receptors was confirmed by performing
experiments in CB1and CB2knock out mice.
Targeting FAAH is of particular interest since it increases AEA,
N-acylethanolamines,levels withouttriggering
0968-0896/$ - see front matter ? 2011 Elsevier Ltd. All rights reserved.
⇑Corresponding author. Tel.: +33 320964374; fax: +33 320964906.
E-mail address: email@example.com (R. Millet).
Bioorganic & Medicinal Chemistry 19 (2011) 3777–3786
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Page 2
activation.13It is noteworthy that these side effects represent a
real curb for the use of CB1-interacting ligands in therapeutic.
Thus, inhibitors of FAAH account for a real option to elicit the
pharmacological effects of CB1receptor activation, while avoiding
CNS side effects.
In this context, we undertook the development of a new series
of FAAH inhibitors based on a 3-carboxamido-5-aryl-isoxazole
scaffold, which general structure is shown in Figure 1. We chose
this template because:
effectsassociated withcentral CB1
(i) Amide derivatives represent an extension and an alternative
a-ketoheterocycles (OL-135),14
(URB597) and ureas (PF622)16usually described as potent
FAAH inhibitors;
aryl carbamates15
(ii) Isoxazole rings have never been described as FAAH inhibi-
tors and the interactions with the enzyme are expected to
be different to the one observed with a-ketooxazoles, since
it has been shown that small changes in the nature of the
heterocycle result in huge differences in activity.16
The amide function introduced at the C-3 position of the isoxaz-
ole was hypothesized to interact with Ser241 of the Ser–Ser–Lys
catalytic triad of FAAH and the aryl group in C-5 position, to fill
in the wide hydrophobic pocket (acyl binding pocket) of the en-
zyme.17Finally, we introduced different aromatic groups, more
or less distant from the carboxamide function at position 3, to
complete the structure–activity relationships.
The FAAH inhibitory potential of the newly synthesized
compounds was evaluated and our lead was then assayed in the
Ar :
Figure 1. General structure of novel 3-amido-5-aryl-isoxazole derivatives compared to URB597, OL-135 and ureas (compound A).
V. Andrzejak et al./Bioorg. Med. Chem. 19 (2011) 3777–3786
Page 3
experimental model of TNBS-induced colitis (TNBS: 2,4,6-trinitro-
benzene sulfonic acid), allowing the identification of a new FAAH
inhibitor endowed with anti-inflammatory properties in the gut.
2. Results and discussion
2.1. Synthesis of inhibitors
The target 3-carboxamido-5-aryl-isoxazoles 30–48 were ob-
tained in four steps from arylketones, as described in Scheme 1.
When the aromatic ketones were not commercially available a
preliminary additional step, consisting in a Suzuki coupling
reaction, was used (compounds 1 and 2). Then, arylketones
underwent a Claisen condensation to afford 1,3-diketoesters
3–11, obtained in their enol forms, in variable yields (37–99%).
Cyclisation into 3-carboxylate-5-aryl-isoxazole (compounds 12–
20) was carried out by addition of hydroxylamine hydrochloride
on 1,3-diketoesters as previously described.18The target com-
pounds 30–48 were finally obtained in moderate yields (47–
80%), by saponification of the ethyl ester function of compounds
12–21 with sodium hydroxide followed by amidification under
peptide coupling conditions (HOBt/HBTU).
2.2. In vitro pharmacology
Thenovel 3-carboxamido-5-aryl-isoxazoleshavebeen
evaluated for their ability to inhibit the hydrolysis of [3H]-AEA by
a recombinant human FAAH preparation.19–21Inhibitory data are
summarized in Table 1.
From a structure–activity relationship perspective, compounds
can be divided into two series, depending on their aromatic termi-
nal group borne by the carboxamide at C-3 position: compounds
30–36 and 45–46 possess a phenyl terminal group (series A)
whereas compounds 37–44 and 47–48 are characterized by a
1,3-benzodioxolyl moiety.
We started our investigations by evaluating the importance of
the substituent borne by the amide at C-3. This first part of the
study was carried out with a 4-biphenyl at C-5 position since this
group generally led to compounds with high affinity for FAAH.17
Thus, compounds 32, 39 and 45–48 were synthesized allowing
the emergence of some interesting SAR. Indeed, in the series A,
the increase of the chain length led to a 200-fold improvement of
the activity with IC50values decreasing from 105 lM for 45 (benzyl
group), to 0.501 lM for 32 (phenylpropyl group). As for the series
B, no significant difference was observed between the activities of
compound 47 (1,3-benzodioxolyl) and 48 ((1,3-benzodioxol-
yl)methyl). More surprisingly, a sharp increase (>1000-fold) of
activity was noticed when the (1,3-benzodioxolyl)methyl of com-
pound 48 (IC50= 92.1 lM) was replaced with the (1,3-benzodioxol-
yl)ethyl moiety (compound 39, IC50= 0.088 lM). It is noteworthy
that when direct comparison was possible, compounds from series
1-2 and commercially
available arylketones
Scheme 1. Reagents and conditions: (a) phenylboronic acid, K2CO3, DME/H2O (1:1),
rt, 48 h; (b) diethyl oxalate, sodium ethanolate, EtOH, reflux, 2 h; (c) hydroxylamine
hydrochloride, EtOH, reflux, 2 h; (d) sodium hydroxide, EtOH (95%), rt, 24 h; (e)
R–NH2, HBTU, HOBt, DIPEA, CH2Cl2, rt, 24 h.
Table 1
Structures and inhibitory activities of compounds 30–48a
CompoundsArRIC50(lM) or FAAH (% inhibition)
251 ± 41 lM
0.50 ± 0.1 lM
12.6 ± 1.5 lM
125 ± 31 lM
25.1 ± 6.0 lM
25.1 ± 3.7 lM
39.8 ± 5.1 lM
0.088 ± 0.004 lM
10.0 ± 0.4 lM
79.4 ± 14 lM
20.0 ± 2.2 lM
43.8 ± 4.8 lM
105.0 ± 15 lM
70.0 ± 10 lM
57.5 ± 8.5 lM
92.1 ± 18 lM
aData represent the mean ± SEM of three experiments performed in duplicate.
V. Andrzejak et al./Bioorg. Med. Chem. 19 (2011) 3777–3786
Page 4
B (37–42) exhibit higher affinities for FAAH than their counterparts
in the series A (30–36). This significant difference of activity is
probably due to the ability of the 1,3-benzodioxolyl group to estab-
lish hydrogen bonds with the protein.
These data demonstrate that the activity is very sensitive to the
nature of the terminal aromatic group borne by the carboxamide at
position 3, as well as the length of the carbon chain linking this
terminal group to the heterocyclic core. Consequently, for the sec-
ond part of the study, we decided to retain the phenylpropyl and
(1,3-benzodioxolyl)ethyl group as 3-carboxamido substituent, for
the series A and B, respectively.
Next, we sought to evaluate the impact of the aromatic substitu-
ent at C-5 position of the isoxazole ring by replacing the 4-biphenyl
moiety by other aromatic groups (compounds 30–31, 33–38, and
40–42). Unfortunately, regardless to the C-3 substituent, this strat-
egy resulted in compounds with only moderate or no affinity for
FAAH. Indeed, introducing bromine, methyl or trifluoromethyl in
place of one phenyl of the 4-biphenyl group (e.g., compare com-
pounds 38, 41 and 42 vs 39) resulted in a drastic reduction in FAAH
inhibition. Analogously, the rigidification of the 4-biphenyl into 2-
phenantryl as well as its replacement with a phenyl or a 2-naphtyl
group did not improve FAAH activity. Finally, we replaced the 4-
biphenylmoietybyits positionisomers inorder to study the impor-
tance of the biphenyl substitution. By comparison with compound
39 (IC50= 0.088 lM), this modification resulted in a strong reduc-
tion of the affinity as for the 3-biphenyl group (43, IC50= 43.8 lM),
data demonstrate that at C-5 position of the isoxazole ring, the 4-
inhibitory activity was detected for our lead compound (39) when
assayed at concentrations up to 30 lM (i.e., at a concentration more
than 300 times higher than its FAAH IC50).
In conclusion, compound 39, characterized by a 4-biphenyl
group at C-5 position and a (1,3-benzodioxolyl)ethyl carboxamido
substituent at position 3 of the isoxazole ring, was found to be the
most potent FAAH inhibitor of our series with an IC50value of
0.088 lM. Thus, we next conducted in silico modeling studies to
enhance our understanding of the mechanism of action of 39.
2.3. In silico study
Docking procedures in the FAAH enzyme have been performed
in order to identify key interactions of compound 39 with the en-
zyme in comparison with the binding mode of OL-135, a reference
inhibitor. Thus the holo-enzyme FAAH co-crystallized with OL-135
covalent inhibitor has been used as the target (1WJ1 PDB entry).25
Prior GOLD docking procedures26have permitted to recover the
within a 2 Å RMSd (data not shown here) in comparison with its co-
crystallized conformation. As this is a covalently bound molecule,
this process assumed a modified ligand by docking its intermedi-
ate-type diol conformation and replacing the Ser241 by an Alanine
residue in order to mimic the electrophile addition of the serine
hydroxyle group by the ligand carbonyle.27As the binding mecha-
nism of 39 is not known, the docking of the compound was tested
in both wild-type and alanine-mutated targets from its initial car-
boxamidoor amino–methanediol forms, respectively. In both cases,
the best GoldScore solutions of the most representative binding
mode are so similar that only the carboxamide form of 39 is repre-
sented as docked in the wild-type FAAH receptor (Fig. 2).
In comparison with OL-135, the polar isoxazole-carboxamide
moiety of compound 39 fits in the oxyanion hole establishing
hydrogen bonds Lys142—carbonyl and Ile138—isoxazole. Never-
theless, it makes the benzodioxol chain binding further in a region
of the entrance cavity not occupied by OL-135. Note that the dock-
ing results reflect some of the structure–affinity relationships
found in the inhibition assays. Indeed, the optimal length for the
linker of the 2-(benzo[d][1,3]dioxol-5-yl) substituent is of 2 meth-
ylenes, compared to one methylene (compound 48) of none (com-
47). Inaddition, the
benzodioxol allow an additional hydrogen bond with Gln273—
compared to the phenyl of compound 32 - which could explain
the significant gain of binding. Also, as for the OL-135, the more
hydrophobic group—4-biphenyl—is reasonably fitting in the ABP
(acyl binding pocket). However, in contrast with the acylphenyl
chain of OL-135 which is flexible enough to fit toward the
membrane access channel, the intrinsic rigid conformation of
hydrogenbond acceptorsof
Figure 2. In silico binding mode of compound 39. The best docking solution of the compound 39 (left) is compared to the co-crystallized OL-135 reference compound (right).
They are represented as sticks in yellow and magenta, respectively, as well as the covalently bound Ser241 in white. The intermolecular hydrogen bonds are displayed in
yellow dashed lines whereas intermolecular van der Waals interactions are implicitly associated to the shape of the solvent-accessible binding site, colored from blue for
polar areas to brown for lipophilic areas. Graphical inspection of models was performed on the SYBYL 6.9.2 software.28
V. Andrzejak et al./Bioorg. Med. Chem. 19 (2011) 3777–3786
Page 5
4-biphenyl constraints the docking of the terminal phenyl in a sub-
pocket thus establishing an orthogonal p–p aromatic interaction
with Phe194. The bent shape between the oxyanion hole and
ABP regions does not allow the suitable fit of 2-biphenyl (com-
pound 43) and 3-biphenyl (compound 44) which translates in
inactive compounds in the inhibition tests.
Figure 3. The FAAH inhibitor 39 protects against TNBS-induced colitis. (A) Changes in body weight at the day of sacrifice as compared with the day of colitis induction. (B)
Macroscopic score of the colonic tissue according to Wallace criteria. (C) MGG-stained colonic tissue of mice challenged with TNBS and treated with vehicle or 39. Histology of
vehicle treated mice showed massive infiltration of mononuclear cells as well as destruction of crypt architecture (top); histology of 39-treated mice showed almost normal
colonic tissue with minimal infiltration of mononuclear cells (bottom). Original magnification, ?20. (D) Histological score of the colonic tissue of the mice according to Ameho
criteria. (E) and (F) Effect of 39 on TNF and Il-1b mRNA expression levels.
V. Andrzejak et al./Bioorg. Med. Chem. 19 (2011) 3777–3786
Page 6
2.4. In vivo pharmacology
Todemonstratethe potentialofcompound39asan invivoFAAH
inhibitor we investigated the effect of our lead compound in the
mouse model of TNBS-induced colitis. Thus, compound 39 was
administered intraperitoneally once daily at the dosage of 10 mg/
(5-ASA, Pentasa) granules (the standard first-line therapy for pa-
tients with mild-to-moderate ulcerative colitis), mixed in food at
the dosage of 150 mg/kg, and provided ad libitum during all the
course of the experiment, was used as anti-inflammatory positive
control.22Mice were euthanized three days after TNBS administra-
tion and parameters reflecting the degree of inflammation were
Before euthanasia, the body weight loss was evaluated. As can
be seen from Figure 3A, daily treatment with compound 39 signif-
icantly reduced body weight loss generally observed during the
development of TNBS colitis. The colon of each mouse was then
examined and damages were assessed by a semi-quantitative
scoring system.23As shown in Figure 3B, 39 induced a decrease
in colitis macroscopic scores of the same magnitude as the positive
control 5-ASA (47%, 2,2 ± 0,4 vs 4,2 ± 0,5, p 6 001). Moreover,
whereas untreated mice exhibited destruction of crypt architec-
ture and infiltration of mononuclear cells in the colonic lamina
propria, mice treated with compound 39 exhibited only minor epi-
thelial damage or cellular infiltration (Fig. 3C).
This protective effect was confirmed by the histological colitis
scores (Fig. 3D).24Indeed, 39 led to 68% decrease of the colitis his-
tological score as compared to the vehicle (1,4 ± 0,5 vs 4,4 ± 0,9,
p 6 001). Finally, the quantification of colonic TNF and IL1-b mRNA
expression, two cytokines widely involved in the inflammatory re-
sponse leading to epithelial injury, showed that systemic adminis-
induceda potent
comparable to the one observed after treatment with 5-ASA
(Fig. 3E and 3F).
Taken together, these data clearly indicate that our new FAAH
inhibitor is endowed with potent anti-inflammatory properties in
the gut. Our work is consistent with two previous reports that
showed that genetic ablation (FAAH?/? mice) or pharmacological
inhibition of FAAH (using URB597) could provide protection
against experimental colitis.10,11Here, we show that this anti-
inflammatory effect can be obtained with another class of FAAH
inhibitor (different from the carbamate derivative URB597), which
validate FAAH as a promising therapeutic target for the treatment
of colitis.
3. Conclusion
In this paper, we described the first series of carboxamide
derivatives that present FAAH activities. Based on 3-carboxa-
mido-5-aryl-isoxazole scaffolds, the compound presented SAR dif-
ferent from a-ketoheterocycle series. Indeed, different aromatic
substituents were introduced in C-5 position of the isoxazole
and the best activities were found with a 4-biphenyl group. The
importance of the substituent borne by the nitrogen atom of
the amide function was investigated and the best inhibitory
capacities were obtained when the substituent was the (1,3-ben-
zodioxolyl)ethyl group. Docking studies revealed no interaction
with Ser241, suggesting a different binding mode compared to
URB597 or OL-135.
In this series, compound 39 inhibits FAAH with an IC50value of
0.088 lM, without affecting MAGL activity, and efficiently reduces
the inflammation and colon damage in a model of TNBS-induced
colitis in mice, showing evidence that FAAH inhibitors are promis-
ing target for the Inflammatory Bowel Diseases (IBD) treatment.
4. Experimental
4.1. Chemistry
All commercial reagents and solvents were used without further
purification. Analytical thin-layer chromatography was performed
on precoated Kieselgel 60F254 plates (Merck); the spots were lo-
cated by UV (254 and 366 nM) and/or with iodine. Silica gel 60
230–400 meshpurchasedfromMerckwasusedforcolumnchroma-
tography. Preparative thick-layer chromatography (TLC) was per-
formed using silica gel from Merck, the compounds were extracted
were determined with a Büchi 535 capillary apparatus and remain
uncorrected.1H NMR spectra were obtained using a Brücker 300
MHz spectrometer, chemical shift (d) were expressed in ppm rela-
tive to tetramethylsilane used as an internal standard, J values are
bined with a Surveyor MSQ (Thermo Electron) equipped with an
mode. Elementalanalysesfor target compoundswere performedby
the 'Service Central d'Analyses' at the CNRS, Vernaison (France) and
the data were within ±0.4% of the theoretical values.
4.1.1. General procedure for the preparation of 1-(biphenyl-2-
yl)ethanone (1) and 1-(biphenyl-3-yl)ethanone (2)
20- or 30-Bromoacetophenone (10.05 mmol, 1 equiv) and phen-
ylboronic acid (12.04 mmol, 1.2 equiv) were dissolved in a mixture
of DME (30 mL) and H2O (30 mL). Then, K2CO3 (15.08 mmol,
1.5 equiv) and tetrakistriphenylphosphinepalladium (0.05 mol,
0.005 equiv) were added and the mixture was refluxed for 48 h.
After cooling to room temperature, the suspension was filtered
off and the filtrate was extracted with CH2Cl2. The resulting organic
layer was dried over MgSO4and concentrated under reduced pres-
sure. The resulting residue was purified by silica gel column chro-
matography (cyclohexane/AcOEt, 6:4) to afford the corresponding
derivatives 1 and 2.
126.96.36.199. 1-(Biphen-2-yl)ethanone (1).
NMR (DMSO-d6) d 7.60–7.28 (m, 9H), 2.09 (s, 3H). LC/MS (APCI+)
m/z 197.3 (MH+).
Brown oil (31%);
220.127.116.11. 1-(Biphen-3-yl)ethanone (2).
NMR (DMSO-d6) d 8.15 (s, 1H), 7.92–7.36 (m, 8H), 2.61 (s, 3H).
LC/MS (APCI+) m/z 197.3 (MH+).
Yellow oil (17%);
4.1.2. General procedure for the preparation of ethyl 2-hydroxy-
4-oxo-4-aryl-but-2-enoate (3–11)
To a stirred solution of sodium ethanolate freshly prepared from
Na (66.04 mmol, 2 equiv) in 50 mL of absolute EtOH, were added
dropwise, at 50 ?C, the aryl ketone (33.02 mmol, 1 equiv) and the
diethyl oxalate (66.04 mmol, 2 equiv) diluted in 30 mL of absolute
ethyl alcohol. The mixture was refluxed for 2 h. The solvent was
evaporated and the obtained residue was taken up in an aqueous
solution of hydrochloric acid (1N) and stirred for 1 h. Then, it
was extracted with AcOEt and washed with distilled water. The or-
ganic layer was dried over MgSO4and the solvent removed. Finally,
the residue was triturated in cyclohexane to give compounds 3–11.
8.02 (d, 2H, J = 7.7 Hz), 7.67 (t, 1H, J = 7.9 Hz), 7.54 (t, 2H,
J = 7.8 Hz), 7.08 (s, 1H), 3.98 (q, 2H, J = 6.4 Hz), 1.12 (t, 3H,
J = 6.4 Hz). LC/MS (APCI+) m/z 221.2 (MH+).
Orange oil (75%);
1H NMR (DMSO-d6) d 10.68 (s, 1H),
V. Andrzejak et al./Bioorg. Med. Chem. 19 (2011) 3777–3786
Page 7
22.214.171.124. Ethyl 4-(4-bromophenyl)-2-hydroxy-4-oxo-2-butenoate
White solid (74%); mp 65–66 ?C;1H NMR (DMSO-d6) d
10.68 (s, 1H), 8.07–7.88 (m, 4H), 6.99 (s, 1H), 4.42 (q, 2H,
J = 7.2 Hz), 1.47 (t, 3H, J = 7.2 Hz). LC/MS (APCI+) m/z 299.1 (MH)
and 301.2 (MH2+).
d 10.68 (s, 1H), 8.10 (d, 2H, J = 8.8 Hz), 7.76 (d, 2H, J = 8.8 Hz),
7.70–7.64 (m, 2H), 7.55 (m, 3H), 7.15 (s, 1H), 4.46 (q, 2H,
J = 7.2 Hz), 1.47 (t, 3H, J = 7.2 Hz). LC/MS (APCI+) m/z 297.3 (MH+).
Yellow solid (78%); mp 111–112 ?C;1H NMR (DMSO-d6)
d 10.68 (s, 1H), 8.77 (d, 1H, J = 8.8 Hz), 8.74–8.70 (m, 1H), 8.55 (s,
1H), 8.22 (dd, 1H, J = 8.8 Hz, J =1.8 Hz), 7.97–7.93 (m, 1H), 7.84
(m, 2H), 7.77–7.67 (m, 2H), 7.27 (s, 1H), 4.46 (q, 2H, J = 7.2 Hz),
1.47 (t, 3H, J = 7.2 Hz). LC/MS (APCI+) m/z 321.4 (MH+).
Yellow solid (85%); mp 116–117 ?C;1H NMR (DMSO-d6)
10.68 (s, 1H), 8.57 (s, 1H), 8.07–7.88 (m, 4H), 7.68–7.55 (m, 2H),
7.25 (s, 1H), 4.42 (q, 2H, J = 7.2 Hz), 1.47 (t, 3H, J = 7.2 Hz). LC/MS
(APCI+) m/z 271.3 (MH+).
Yellow solid (74%); mp 79–80 ?C;1H NMR (DMSO-d6) d
10.68 (s, 1H), 7.97 (d, 2H, J = 8.2 Hz), 7.38 (d, 2H, J = 8.2 Hz),7.09
(s, 1H), 4.30 (q, 2H, J = 7.1 Hz), 2.37 (s, 1H), 1.31 (t, 3H,
J = 7.0 Hz). LC/MS (APCI+) m/z 235.3 (MH+).
Ethyl 2-hydroxy-4-oxo-4-p-tolyl-but-2-enoate
Orange solid (57%); mp 47–48 ?C;1H NMR (DMSO-d6) d
but-2-enoate (9).
(DMSO-d6) d 10.68 (s, 1H), 8.02 (d, 2H, J = 8.2 Hz), 7.64 (d, 2H,
J = 8.2 Hz), 6.98 (s, 1H), 4.30 (q, 2H, J = 7.3 Hz), 1.30 (t, 3H,
J = 7.3 Hz). LC/MS (APCI+) m/z 289.2 (MH+).
Yellow solid (99%); mp 50–51 ?C;1H NMR
10.68 (s, 1H), 7.74–7.31 (m, 10H), 4.35 (q, 2H, J = 7.2 Hz), 1.14 (t,
3H, J = 7.1 Hz). LC/MS (APCI+) m/z 297.3 (MH+).
Brown solid (37%); mp 63–64 ?C;1H NMR (DMSO-d6) d
10.68 (s, 1H), 8.08–6.73 (m, 10H), 4.29 (q, 2H, J = 7.0 Hz), 1.27
(m, 3H). LC/MS (APCI+) m/z 297.3 (MH+).
Brown solid (83%); mp 75–76 ?C;1H NMR (DMSO-d6) d
4.1.3. General procedure for the preparation of ethyl 5-aryl-isox
azole-3-carboxylate (12–20)
A solution of compound 3–11 (1 equiv) and hydroxylamine
hydrochloride (1 equiv) in absolute EtOH was stirred and re-
fluxed for 2 h. At the end of the reaction, the solvent was re-
moved and the residue was purified by flash chromatography
cyclohexane/AcOEt (8:2, v/v) followed by crystallization in abso-
lute EtOH.
22.214.171.124. Ethyl 5-phenyl-isoxazole-3-carboxylate (12).
solid (82%); mp 59–60 ?C;1H NMR (DMSO-d6) d 7.52–7.48 (m, 5H),
7.13 (s, 1H), 4.29 (q, 2H, J = 7.3 Hz), 1.30 (t, 3H, J = 7.2 Hz). LC/MS
(APCI+) m/z 218.2 (MH+).
d 7.93 (d, 2H, J = 8.5 Hz), 7.78 (d, 2H, J = 8.5 Hz), 7.58 (s, 1H), 4.39
(q, 2H, J = 7.1 Hz), 1.34 (t, 3H, J = 7.1 Hz). LC/MS (APCI+) m/z 296.1
(MH) and 298.2 (MH2+).
White solid (85%); mp 133–134 ?C;1H NMR (DMSO-d6)
d 8.30 (d, 2H, J = 8.5 Hz), 7.75 (d, 2H, J = 8.5 Hz), 7.48–7.46 (m,
3H), 7.25 (d, 2H, J = 8.5 Hz), 7.15 (s, 1H), 4.35 (q, 2H, J = 7.2 Hz),
1.32 (t, 3H, J = 7.2 Hz). LC/MS (APCI+) m/z 294.4 (MH+).
White solid (87%); mp 117–118 ?C;1H NMR (DMSO-d6)
d6) d 8.75 (d, 2H, J = 6.4 Hz), 8.65 (s, 1H), 8.24 (d, 1H, J = 9.0 Hz),
8.13 (m, 2H), 8.00 (d, 1H, J = 8.7 Hz), 7.65 (s, 1H), 7.59–7.56 (m,
2H), 4.42 (q, 2H, J = 7.3 Hz), 1.37 (t, 3H, J = 7.0 Hz). LC/MS (APCI+)
m/z 318.4 (MH+).
Yellow solid (90%); mp 196–197 ?C;
d 8.60 (s, 1H), 8.11–8.06 (m, 3H), 8.03–7.98 (m, 1H), 7.64–7.62
(m, 2H), 7.61 (s, 1H), 4.41 (q, 2H, J = 7.0 Hz), 1.37 (t, 3H,
J = 7.1 Hz). LC/MS (APCI+) m/z 268.3 (MH+).
White solid (92%); mp 107–108 ?C;1H NMR (DMSO-d6)
220.127.116.11. Ethyl 5-p-tolyl-isoxazole-3-carboxylate (17).
solid (86%); mp 59–60 ?C;
J = 8.2 Hz), 7.42 (s, 1H), 7.37 (d, 2H, J = 8.0 Hz), 4.38 (q, 2H,
J = 7.1 Hz), 2.37 (s, 3H), 1.34 (t, 3H, J = 7.1 Hz). LC/MS (APCI+) m/z
1H NMR (DMSO-d6) d 7.84 (d, 2H,
18.104.22.168. Ethyl 5-(4-trifluoromethyl-phenyl)-isoxazole-3-carbox-
ylate (18).
White solid (73%); mp 136–137 ?C;
(DMSO-d6) d 8.42 (d, 2H, J = 8.2 Hz), 8.36 (d, 2H, J = 8.2 Hz), 7.85
(s, 1H), 4.39 (q, 2H, J = 7.2 Hz), 1.38 (t, 3H, J = 7.2 Hz). LC/MS (APCI+)
m/z 286.2 (MH+).
7.89 (d, 1H, J = 7.0 Hz), 7.55–7.51 (m, 2H), 7.49–7.40 (m, 4H),
7.30–7.25 (m, 2H), 5.90 (s, 1H), 4.38 (q, 2H, J = 7.3 Hz), 1.39 (t,
3H, J = 7.3 Hz). LC/MS (APCI+) m/z 294.4 (MH+).
White solid (74%); mp 72–73 ?C;
1H NMR (CDCl3) d
8.26 (s, 1H), 7.96–7.42 (m, 8H), 7.78 (s, 1H), 4.42 (q, 2H,
J = 7.3 Hz), 1.36 (t, 3H, J = 7.2 Hz). LC/MS (APCI+) m/z 294.4 (MH+).
White solid (60%); mp 75–76 ?C;1H NMR (DMSO-d6) d
4.1.4. General procedure for the preparation of 5-aryl-isoxazole-
3-carboxylic acid (21–29)
To a stirred solution of ester 12–20 (1 equiv) in EtOH (95%), was
added sodium hydroxide in pellets (10 equiv). The mixture was
then stirred at room temperature for 24 h. EtOH was removed un-
der reduced pressure and the residue was acidified (1N HCl, pH 2)
and extracted with EtOAc. The organic extracts were washed with
water and brine, dried over MgSO4and concentrated under re-
duced pressure to afford essentially pure carboxylic acid 21–29.
184.108.40.206. 5-Phenyl-isoxazole-3-carboxylic acid (21).
solid (79%); mp 163–164 ?C;1H NMR (DMSO-d6) d 12.79 (s, 1H),
7.96–7.93 (m, 2H), 7.59–7.53 (m, 3H), 7.41 (s, 1H). LC/MS (APCI+)
m/z 190.2 (MH+).
d 12.81 (s, 1H), 7.89 (d, 2H, J = 8.1 Hz), 7.76 (d, 2H, J = 8.0 Hz),
7.48 (s, 1H). LC/MS (APCI+) m/z 268.1 (MH) and 270.2 (MH2+).
White solid (83%); mp 226–227 ?C;1H NMR (DMSO-d6)
d6) d 12.80 (s, 1H), 8.30 (d, 2H, J = 8.1 Hz), 7.75 (d, 2H, J = 8.5 Hz),
Yellow solid (61%); mp 212–213 ?C;
V. Andrzejak et al./Bioorg. Med. Chem. 19 (2011) 3777–3786
Page 8
7.48–7.46 (m, 3H), 7.38 (s, 1H), 7.25 (d, 2H, J = 8.2 Hz). LC/MS
(APCI+) m/z 266.3 (MH+).
d6) d 12.81 (s, 1H), 8.75 (d, 1H, J = 8.2 Hz), 8.66 (s, 1H), 8.23 (d,
2H, J = 8.3 Hz), 8.12 (m, 2H), 8.02 (m, 1H), 7.60–7.57 (m, 2H),
7.54 (s, 1H). LC/MS (APCI+) m/z 290.3 (MH+).
Yellow solid (84%); mp 220–221 ?C;
d 12.79 (s, 1H), 8.57 (s, 1H), 8.09–7.97 (m, 4H), 7.63–7.58 (m,
2H), 7.53 (s, 1H). LC/MS (APCI+) m/z 240.2 (MH+).
White solid (84%); mp 208–209 ?C;1H NMR (DMSO-d6)
22.214.171.124. 5-p-Tolyl-isoxazole-3-carboxylic acid (26).
lid (91%); mp 165–166 ?C;1H NMR (DMSO-d6) d 12.81 (s, 1H), 7.82
(d, 2H, J = 8.2 Hz), 7.35 (d, 2H, J = 8.2 Hz), 7.31 (s, 1H), 2.36 (s, 1H).
LC/MS (APCI+) m/z 204.2 (MH+).
Beige so-
acid (27).
(DMSO-d6) d 12.80 (s, 1H), 8.17 (d, 2H, J = 7.9 Hz), 7.93 (d, 2H,
J = 7.9 Hz), 7.62 (s, 1H). LC/MS (APCI+) m/z 258.2 (MH+).
White solid (87%); mp 201–202 ?C;
d 12.79 (s, 1H), 7.82 (d, 2H, J = 6.1 Hz), 7.60–7.40 (m, 5H), 7.24
(m, 2H), 6.27 (s, 1H). LC/MS (APCI+) m/z 266.3 (MH+).
White solid (88%); mp 110–111 ?C;1H NMR (DMSO-d6)
d 12.79 (s, 1H), 8.23 (s, 1H), 7.93 (d, 1H, J = 7.9 Hz), 7.84–7.41 (m,
7H), 7.61 (s, 1H). LC/MS (APCI+) m/z 266.3 (MH+).
White solid (75%); mp 180–181 ?C;1H NMR (DMSO-d6)
4.1.5. General procedure for the preparation of 5-aryl-isoxazole-
3-carboxamide (30–48)
To a solution of carboxylic acid 21–29 (1 equiv) in anhydrous
weresuccessively added
(0.5 equiv) and DIPEA (2 equiv). The mixture was stirred for
45 min at room temperature. Then, the appropriate amine
(1.1 equiv) was introduced and the stirring was continued for
24 h. At the end of the reaction, the mixture was filtered off
and the filtrate was successively washed with saturated aqueous
NaHCO3 solution, 1N aqueous HCl and distilled water. The or-
ganic layer was dried over MgSO4and was concentrated in va-
cuo. The resulting residue was purified by TLC (cyclohexane/
AcOEt, 7:3) and crystallized in absolute EtOH to give carboxam-
ide 30–48.
HBTU (1.5 equiv),HOBt
d 8.85 (t, 1H, J = 5.5 Hz), 7.93 (d, 2H, J = 8.2 Hz), 7.91–7.53 (m,
3H), 7.31 (s, 1H), 7.28–7.14 (m, 5H), 3.29 (t, 2H, J = 5.8 Hz), 2.62
(t, 2H, J = 7.6 Hz), 1.83 (m, 2H). LC/MS (APCI+) m/z 307.2 (MH+);
Anal. Calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C,
White solid (67%); mp 127–128 ?C;1H NMR (DMSO-d6)
18.104.22.168. 5-(4-Bromophenyl)-N-(3-phenylpropyl)isoxazole-3-car-
boxamide (31).
White solid (63%); mp 171–172 ?C;1H NMR
(DMSO-d6) d 10.93 (t, 1H, J = 5.7 Hz), 9.94 (d, 2H, J = 8.7 Hz), 9.82 (d,
J = 8.7 Hz), 9.47 (s, 1H), 9.36–9.20 (m, 5H), 5.34 (t, 2H,
J = 5.7 Hz), 4.58 (t, 2H, J = 7.6 Hz), 3.89 (m, 2H). LC/MS (APCI+) m/
z 385.1 (MH) and 387.3 (MH2+); Anal. Calcd for C19H17BrN2O2: C,
59.24; H, 4.45; N, 7.27. Found: C, 59.36; H, 4.33; N, 7.18.
220.127.116.11. 5-(Biphen-4-yl)-N-(3-phenylpropyl)isoxazole-3-carbox-
amide (32).
White solid (52%); mp 142–143 ?C;
(DMSO-d6) d 8.56 (ls, 1H), 8.30 (d, 2H, J = 8.7 Hz), 7.75 (d, 2H,
J = 8.5 Hz), 7.48–7.46 (m, 3H), 7.36 (s, 1H), 7.25 (d, 2H, J = 8.7 Hz),
7.20–7.17 (m, 5H), 3.18 (q, 2H, J = 5.5 Hz), 2.94 (t, 2H, J = 7.2 Hz),
2.10 (m, 2H). LC/MS (APCI+) m/z 383.3 (MH+); Anal. Calcd for
C25H22N2O2: C, 78.51; H, 5.80; N, 7.32. Found: C, 78.44; H, 5.66;
220.127.116.11. 5-(Phenanthr-2-yl)-N-(3-phenylpropyl)isoxazole-5-car-
boxamide (33).
Yellow solid (72%); mp 186–187 ?C;
8.91 (t,
J = 7.9 Hz), 8.65 (s, 1H), 8.24 (d, 1H, J = 9.0 Hz), 8.14–8.11 (m,
2H), 7.99 (d, 1H, J = 8.7 Hz), 7.59–7.56 (m, 2H), 7.51 (s, 1H),
7.31–7.15 (m,5H),3.31 (q,
J = 7.7 Hz), 1.86 (m, 2H). LC/MS (APCI+) m/z 407.2 (MH+); Anal.
Calcd for C27H22N2O2: C, 79.78; H, 5.46; N, 6.89. Found: C,
J = 5.7 Hz), 8.74(d,
J = 5.5 Hz), 2.64(t,2H,
amide (34).
(DMSO-d6) d 8.89 (t, 1H, J = 5.5 Hz), 8.56 (s, 1H), 8.08 (d, 2H,
J = 7.9 Hz), 8.02–7.98 (m, 2H), 7.63–7.61 (m, 2H), 7.46 (s, 1H),
7.29–7.18 (m, 5H), 3.31 (q, 2H, J = 5.5 Hz), 2.63 (t, 2H, J = 7.6 Hz),
1.85 (m, 2H). LC/MS (APCI+) m/z 357.3 (MH+); Anal. Calcd for
C23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found: C, 77.44; H, 5.60;
White solid (47%); mp 160–161 ?C;
d 8.83 (t, 1H, J = 5.7 Hz), 7.81 (d, 2H, J = 8.2 Hz), 7.35 (d, 2H,
J = 8.2 Hz), 7.31–7.17 (m, 6H), 3.27 (q, 2H, J = 6.9 Hz), 2.62 (t, 2H,
J = 7.7 Hz), 2.37 (s, 3H), 1.83 (m, 2H). LC/MS (APCI+) m/z 312.2
(MH+); Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74.
Found: C, 75.11; H, 5.95 N, 8.69.
White solid (80%); mp 150–151 ?C;1H NMR (DMSO-d6)
220.127.116.11. 5-(4-(Trifluoromethyl)phenyl)-N-(3-phenylpropyl) isox-
azole-3-carboxamide (36).
157 ?C;1H NMR (DMSO-d6) d 8.93 (t, 1H, J = 5.7 Hz), 8.15 (d, 2H,
J = 8.2 Hz), 7.93 (d, 2H, J = 8.3 Hz), 7.56 (s, 1H), 7.31–7.15 (m, 5H),
3.28 (q, 2H, J = 6.9 Hz), 2.62 (t, 2H, J = 7.6 Hz), 1.83 (m, 2H). LC/
MS (APCI+) m/z 375.4 (MH+); Anal. Calcd for C20H17F3N2O2: C,
64.17; H, 4.58; N, 7.48. Found: C, 64.22; H, 4.71; N, 7.22.
White solid (55%); mp 156–
126.96.36.199. N -(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5-phenyl-isoxaz-
192 ?C;1H NMR (DMSO-d6) d 8.56 (t, 1H, J = 5.5 Hz), 7.91 (d, 2H,
J = 8.2 Hz), 7.85–7.74 (m, 3H), 7.56 (s, 1H), 6.93 (d, 1H, J = 8.5 Hz),
6.77 (s, 1H), 6.67 (d, 1H, J = 8.5 Hz), 6.06 (s, 2H), 3.45 (q, 2H,
J = 6.9 Hz), 2.81 (t, 2H, J = 7.1 Hz). LC/MS (APCI+) m/z 337.2
(MH+); Anal. Calcd for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33.
Found: C, 67.77; H, 5.00 N, 8.39.
solid (65%);mp 191–
126.96.36.199. N -(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5-(4-bromophe-
nyl)-isoxazole-3-carboxamide (38).
205–206 ?C;1H NMR (DMSO-d6) d 8.83 (t, 1H, J = 5.5 Hz), 7.87 (d,
2H, J = 8.7 Hz), 7.75 (d, 2H, J = 8.5 Hz), 7.39 (s, 1H), 6.82–6.81 (m,
2H), 6.68 (d, 1H, J = 7.9 Hz), 5.96 (s, 2H), 3.45 (q, 2H, J = 6.8 Hz),
2.81 (t, 2H, J = 7.3 Hz). LC/MS (APCI+) m/z 415.2 (MH) and 417.3
(MH2+); Anal. Calcd for C19H15BrN2O4: C, 54.96; H, 3.64; N, 6.75.
Found: C, 55.01; H, 3.68 N, 6.82.
White solid (68%); mp
220.127.116.11. N-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5-(biphen-4-yl)-
isoxazole-3-carboxamide (39).
200 ?C; H NMR (DMSO-d6) d 8.84 (t, 1H, J = 5.5 Hz), 8.02 (d, 2H,
J = 8.5 Hz), 7.85 (d, 2H, J = 8.5 Hz), 7.75 (d, 2H, J = 7.3 Hz), 7.51 (t,
White solid (72%); mp 199–
V. Andrzejak et al./Bioorg. Med. Chem. 19 (2011) 3777–3786
Page 9
2H, J = 7.4 Hz), 7.41 (t, 1H, J = 7.7 Hz), 7.38 (s,1H), 6.83–6.81(m,2H),
6.69(d,1H,J = 7.9 Hz),5.96(s,2H),3.46(q,2H,J = 6.4 Hz),2.77(t,2H,
J = 7.3 Hz). LC/MS (APCI+) m/z 413.1 (MH+); Anal. Calcd for
22.214.171.124. N -(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5-(napht-2-yl)-
isoxazole-3-carboxamide (40).
205 ?C;1H NMR (DMSO-d6) d 8.88 (t, 1H, J = 5.7 Hz), 8.56 (s, 1H),
8.08 (d, 2H, J = 7.6 Hz), 8.02–7.98 (m, 2H), 7.63–7.60 (m, 2H),
7.45 (s, 1H), 6.85–6.83 (m, 2H), 6.69 (d, 1H, J = 7.7 Hz), 5.96 (s,
2H), 3.47 (q, 2H, J = 6.7 Hz), 2.79 (t, 2H, J = 7.3 Hz). LC/MS (APCI+)
m/z 387.2 (MH+); Anal. Calcd for C23H18N2O4: C, 71.49; H, 4.70;
N, 7.25. Found: C, 71.22; H, 4.81 N, 7.53.
White solid (31%); mp 204–
220.127.116.11. N-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5-p-tolyl-isoxaz-
ole-3-carboxamide (41).
White solid (45%); mp 187–188 ?C;
1H NMR (DMSO-d6) d 8.79 (t, 1H, J = 5.4 Hz), 7.80 (d, 2H, J = 8.2 Hz),
7.35 (d, 2H, J = 8.2 Hz), 7.25 (s, 1H), 6.83–6.81 (m, 2H), 6.67 (d, 1H,
J = 7.9 Hz), 5.96 (s, 2H), 3.44 (q, 2H, J = 6.5 Hz), 2.76 (t, 2H,
J = 7.3 Hz), 2.37 (s, 3H). LC/MS (APCI+) m/z 351.4 (MH+); Anal. Calcd
for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.72; H, 5.02
220.127.116.11. N -(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5-(4-(trifluoro-
methyl)phenyl)-isoxazole-3-carboxamide (42).
(38%); mp 187–188 ?C;
J = 5.8 Hz), 8.15 (d, 2H, J = 8.2 Hz), 7.92 (d, 2H, J = 8.2 Hz), 7.54 (s,
1H), 6.81 (m, 2H), 6.68 (d, 1H, J = 8.2 Hz), 5.96 (s, 2H), 3.45 (q,
2H, J = 6.7 Hz), 2.77 (t, 2H, J = 7.3 Hz). LC/MS (APCI+) m/z 405.3
(MH+); Anal. Calcd for C20H15F3N2O4: C, 59.41; H, 3.74; N, 6.93.
Found: C, 59.28; H, 3.88 N, 7.03.
White solid
1H NMR (DMSO-d6) d 8.89 (t, 1H,
220.127.116.11. N -(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5-(biphen-2-yl)-
isoxazole-3-carboxamide (43).
138 ?C;1H NMR (DMSO-d6) d 8.44 (t, 1H, J = 7.2 Hz), 7.79 (m, 2H),
7.54–7.28 (m, 8H), 6.93–6.77 (m, 3H), 6.07 (s, 2H), 3.49 (q, 2H,
J = 6.4 Hz), 2.81 (t, 2H, J = 7.2 Hz). LC/MS (APCI+) m/z 413.1
(MH+); Anal. Calcd for C25H20N2O4: C, 72.80; H, 4.89; N, 6.79.
Found: C, 72.66; H, 4.95 N, 6.55.
White solid (18%); mp 137–
184.108.40.206. N -(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5-(biphen-3-yl)-
isoxazole-3-carboxamide (44).
150 ?C;1H NMR (DMSO-d6) d 8.76 (t, 1H, J = 7.2 Hz), 8.21 (s, 1H),
7.93–7.39 (m, 9H), 6.82 (s, 1H), 6.72–6.69 (m, 2H), 5.96 (s, 2H),
3.46 (q, 2H, J = 6.4 Hz), 2.77 (t, 2H, J = 7.3 Hz). LC/MS (APCI+) m/z
413.1 (MH+); Anal. Calcd for C25H20N2O4: C, 72.80; H, 4.89; N,
6.79. Found: C, 72.92; H, 5.01 N, 6.48.
White solid (64%); mp 149–
18.104.22.168. 5-(Biphen-4-yl)-N-(3-benzyl)isoxazole-3-carboxamide
White solid (31%); mp 195–196 ?C;1H NMR (DMSO-d6)
d 9.40 (t, 1H, J = 6.1 Hz), 8.02 (d, 2H, J = 8.4 Hz), 7.85 (d, 2H,
J = 8.2 Hz), 7.75 (d, 2H, J = 7.2 Hz), 7.52–7.23 (m, 9H), 4.47 (d, 2H,
J = 6.4 Hz). LC/MS (APCI+) m/z 355.4 (MH+); Anal. Calcd for
C23H18N2O2: C, 77.95; H, 5.12; N, 7.90. Found: C, 77.78; H, 5.34
amide (46).
(DMSO-d6) d 8.89 (t, 1H, J = 5.8 Hz), 8.00 (d, 2H, J = 8.2 Hz), 7.85
(d, 2H, J = 8.5 Hz), 7.75 (d, 2H, J = 7.3 Hz), 7.53–7.20 (m, 9H), 3.50
(q, 2H, J = 6.7 Hz), 2.86 (t, 2H, J = 7.57 Hz). LC/MS (APCI+) m/z
369.4 (MH+); Anal. Calcd for C24H20N2O2: C, 78.24; H, 5.47; N,
7.60. Found: C, 78.51; H, 5.72 N, 7.59.
White solid (26%); mp 210–211 ?C;
184.108.40.206. N-(Benzo[d][1,3]dioxol-5-yl)-5-(biphen-4-yl)isoxazole-
3-carboxamide (47).
White solid (24%); mp 215–216 ?C;1H
NMR (DMSO-d6) d 10.70 (s, 1H), 8.05 (d, 2H, J = 8.4 Hz), 7.85 (d,
2H, J = 8.2 Hz), 7.76 (d, 2H, J = 7.0 Hz), 7.53–7.48 (m, 4H), 6.92–
6.81 (m, 3H), 6.02 (s, 2H). LC/MS (APCI+) m/z 385.4 (MH+); Anal.
Calcd for C23H16N2O4: C, 71.87; H, 4.20; N, 7.29. Found: C, 71.59;
18.104.22.168. N -(2-(Benzo[d][1,3]dioxol-5-yl)methyl)-5-(biphen-4-
yl)-isoxazole-3-carboxamide (48).
197–198 ?C;1H NMR (DMSO-d6) d 9.34 (t, 1H, J = 6.1 Hz), 8.02 (d,
2H, J = 8.4 Hz), 7.85 (d, 2H, J = 8.2 Hz), 7.75 (d, 2H, J = 7.3 Hz),
7.52–7.39 (m, 4H), 6.91–6.80 (m, 3H), 5.98 (s, 2H), 4.35 (d, 2H,
J = 6.1 Hz). LC/MS (APCI+) m/z 399.4 (MH+); Anal. Calcd for
C24H18N2O4: C, 72.35; H, 4.55; N, 7.03. Found: C, 72.21; H, 4.58
White solid (17%); mp
4.2. In vitro assays towards human FAAH and MAGL
Tubes containing human recombinant FAAH (expressed in E.
Coli) in buffer (100 mM Tris–HCl, 1 mM EDTA, 0.1% (w/v) BSA, pH
7.4, 165 lL), test compounds in DMSO, or DMSO alone for controls
(10 lL), and [3H]-AEA (50 000 dpm, 2 lM final concentration,
25 lL) were incubated at 37 ?C for 10 min. Reactions were stopped
by rapidly adding 400 lL of ice-cold chloroform/methanol (1:1 v/v)
followed by vigorous mixing. Phases were separated by centrifuga-
tion at 850?g, and aliquots (200 lL) of the upper methanol/buffer
phase were counted for radioactivity by liquid scintillation. In all
experiments, tubes containing buffer only were used as control
for chemical hydrolysis (blank) and this value was systematically
subtracted. Using these conditions, the well known FAAH inhibitor
URB597 inhibits hFAAH with an IC50value of 40 nM. MAGL inhibi-
tion was assayed using a similar protocol but with purified hMAGL
and[3H]-2-OG (10 lM) instead
of FAAHand[3H]-AEA,
4.3. In vivo Assays
C57Bl6 mice (n = 10 per group) had free access to standard
mouse chow and tap water. For colitis induction, mice were
anesthetized by subcutaneous administration of xylazine–keta-
mine (50 mg/kg) in saline for 90–120 min and received an intra-
rectal administration of TNBS (40 lL, 150 mg/kg) dissolved in a
1:1 mixture of 0.9% NaCl with 100% ethanol. Control mice
(n = 6) received a 1:1 mixture of 0.9% NaCl with 100% ethanol
using the same technique. 5-ASA granules mixed in food at the
dosage of 150 mg/kg and provided ad libitum during all the
course of the experiment was used as anti-inflammatory positive
control. The FAAH inhibitor 39 was dissolved in vehicle (DMSO
2%, Tween 80 1% in saline) and administered intraperitoneally
once daily, starting three days before colitis induction at the dos-
age of 10 mg/kg. Animals were euthanized three days after TNBS
administration. Body-weight changes, macroscopic and histolog-
ical indications of colitis were evaluated blindly by two investi-
gators. The colon of each mouse was examined to evaluate the
macroscopic lesions according to the Wallace criteria.23The Wal-
lace score rates macroscopic lesions on a scale from 0 to 10
based on features reflecting inflammation, such as hyperemia,
thickening of the bowel, and extent of ulceration. A colon spec-
imen located precisely 2 cm above the anal canal was used for
histological evaluation following May–Grunwald Giemsa staining
and according to the Ameho criteria.24This grading on a scale
from 0 to 6 takes into account the degree of inflammation infil-
trate, the presence of erosion, ulceration, or necrosis, and the
depth and surface extension of lesions. The other parts of the co-
lon were frozen and used to quantify cytokines mRNA levels.
V. Andrzejak et al./Bioorg. Med. Chem. 19 (2011) 3777–3786
Page 10
4.4. Quantification of colonic cytokines levels by real-time PCR
Total RNA from colon was extracted using Nucleospin RNAII
(Macherey Nagel, Hoerdt, France) and then reverse transcribed
using the high-Capacity cDNA Reverse Transcription Kit (Applied
Biosystems, Foster City, USA). Real time PCR was performed using
SYBR Green (Applied Biosystems, Foster City, USA). Specific prim-
ers for TNF (TNFa_F_Sou_MBM; CCACCACGCTCTTCTGTCTA and
TNFa_R_Sou_MBM; GAGGCCATTTGGGAACTTCT), IL-1b (IL1b_F_-
AGGCCACAGGTATTTTGTCG) and b-Actin acting as internal control
were designed using the Primer Express Program (Applied Biosys-
tems, Foster City, USA). For graphical representation of quantitative
PCR data, raw cycle threshold values (Ct values) obtained for target
samples were deducted from the Ct value obtained for internal
control transcript levels, using the DDCt method as follows:
DDCt = (Ct,target-Ct,control)treatment-(Ct,target-Ct,control)non-
treatment, and the final data were derived from 2-DDCt.
The authors thank Ms. Perrine Six for the NMR and LC–MS anal-
ysis, as well as Dr. Geoffray Labar for the preparation of the human
recombinant enzymes. This work was financially supported by the
'Conseil Régional Nord Pas de Calais'.
References and notes
1. Vandevoorde, S.; Lambert, D. M. Chem. Biodivers. 2007, 4, 1858.
2. Ahn, K.; McKinney, M. K.; Cravatt, B. F. Chem. Rev. 2008, 108, 1687.
3. Dinh, T. P.; Freund, T. F.; Piomelli, D. A. Chem. Phys. Lipids 2002, 121, 149.
4. Muccioli, G. G. Drug Discovery Today 2010, 15, 474.
5. Izzo, A. A.; Sharkey, K. A. Pharmacol. Ther. 2010, 126, 21.
6. D'Argenio, G.; Valenti, M.; Scaglione, G.; Cosenza, V.; Sorrentini, I.; Di Marzo, V.
7. Wright, K.; Rooney, N.; Feeney, M.; Tate, J.; Robertson, D.; Welham, M.; Ward, S.
Gastroenterology 2005, 129, 437.
8. Marquéz, L.; Suárez, J.; Iglesias, M.; Bermudez-Silva, F. J.; Rodríguez de Fonseca,
F.; Andreu, M. PLoS ONE 2009, 4, e6893.
9. Di Marzo, V.; Izzo, A. Gut 2006, 55, 1373.
10. Storr, M. A.; Keenan, C. M.; Zhang, H.; Patel, K. D.; Makriyannis, A.; Sharkey, K.
A. Inflamm. Bowel. Dis. 2009, 15, 1678.
11. Storr, M. A.; Keenan, C. M.; Emmerdinger, D.; Zhang, H.; Yüce, B.; Sibaev, A.;
Massa, F.; Buckley, N. E.; Lutz, B.; Göke, B.; Brand, S.; Patel, K. D.; Sharkey, K. A.
J. Mol. Med. 2008, 86, 925.
12. Massa, F.; Marsicano, G.; Hermann, H.; Cannich, A.; Monory, K.; Cravatt, B. F.;
Ferri, G. L.; Sibaev, A.; Storr, M.; Lutz, B. J. Clin. Invest. 2004, 113, 1202.
13. Cravatt, B. F.; Lichtman, A. H. Curr. Opin. Chem. Biol. 2003, 7, 469.
14. Garfunkle, J.; Ezzili, C.; Rayl, T. J.; Hochstatter, D. G.; Hwang, I.; Boger, D. L. J.
Med. Chem. 2008, 51, 4392.
15. Mor, M.; Lodola, A.; Rivara, S.; Vacondio, F.; Duranti, A.; Tontini, A.; Sanchini, S.;
Piersanti, G.; Clapper, J. R.; King, A. R.; Tarzia, G.; Piomelli, D. J. Med. Chem.
2008, 51, 3487.
16. Ahn, K.; Johnson, D. S.; Fitzgerald, L. R.; Liimatta, M.; Arendse, A.; Stevenson, T.;
Lund, E. T.; Nugent, R. A.; Nomanbhoy, T. K.; Alexander, J. P.; Cravatt, B. F.
Biochemistry 2007, 46, 13019.
17. Seierstad, M.; Breitenbucher, J. G. J. Med. Chem. 2008, 51, 7327.
18. Andrzejak, V.; Millet, R.; El Bakali, J.; Guelzim, A.; Gluszok, S.; Chavatte, P.;
Bonte, J. P.; Vaccher, C.; Lipka, E. Lett. Org. Chem. 2010, 7, 32.
19. Labar, G.; Vliet, F. V.; Wouters, J.; Lambert, D. M. Amino Acids 2008, 34, 127.
20. Muccioli, G. G.; Labar, G.; Lambert, D. M. Chem. Biol. Chem. 2008, 9, 2704.
21. Muccioli, G. G.; Fazio, N.; Scriba, G. K.; Poppitz, W.; Cannata, F.; Poupaert, J. H.;
Wouters, J.; Lambert, D. M. J. Med. Chem. 2006, 49, 417.
22. Ritland, S. R.; Leighton, J. A.; Hirsch, R. E.; Morrow, J. D.; Weaver, A. L.; Gendler,
S. Clin. Cancer Res. 1999, 5, 855.
23. Wallace, J. L.; MacNaughton, W. K.; Morris, G. P.; Beck, P. L. Gastroenterology
1989, 96, 29.
24. Ameho, C. K.; Adjei, A. A.; Harrison, E. K.; Takeshita, K.; Morioka, T.; Arakaki, Y.;
Ito, E.; Suzuki, I.; Kulkarni, A. D.; Kawajiri, A.; Yamamoto, S. Gut 1997, 41, 487.
25. Mileni, M.; Garfunkle, J.; DeMartino, J. K.; Cravatt, B. F.; Boger, D. L.; Stevens, R.
C. J. Am. Chem. Soc. 2009, 5, 10497.
26. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267,
27. Katritch, V.; Byrd, C. M.; Tseitin, V.; Dai, D.; Raush, E.; Totrov, M.; Abagyan, R.;
Jordan, R.; Hruby, D. E. J. Comput.-Aided Mol. Des. 2007, 21, 549.
28. Tripos Associates, Inc., 1699 South Hanley Road, St. Louis, MO 63144.
V. Andrzejak et al./Bioorg. Med. Chem. 19 (2011) 3777–3786

subset: commoncrawl


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The book is a prose recounting of myths and stories from three eras: Greek and Roman mythology, King Arthur legends, and medieval romances. The stories are interspersed with his own commentary and with quotations from the writings of Bulfinch's contemporaries which contain a reference to the story under discussion. This combination of classical elements and modern literature was novel for his time


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The Skateparks Project
Welcome to The Skateparks Project, soon to be your complete guide to skateparks in the UK.
The Skateparks Project is a skatepark directory, resource and news feed dedicated to the UK skate industry. Not only will you be able to find information about skateparks across the UK, but our dedicated resources are designed to help anyone looking to build a skatepark.
We're set to launch on March 31st so check back soon!


text:
Resort Breckenridge Park Meadows by Ski Country Resorts - Breckenridge
110 Sawmill Road - Breckenridge1-877-662-6988
Located in the mountains in Breckenridge and offering free Wi-Fi, Breckenridge Park Meadows by Ski Country Resorts makes for a great choice for your Breckenridge ski condominium resort.
This Breckenridge condominium resort offers ski storage, concierge services and laundry facilities. If you want low-key dining options, you will be pleased to find barbecue grills and a picnic area.
The lobby has complimentary newspapers, a fireplace, fresh coffee and TV. The reception desk is open during limited hours only. Other amenities include an area shuttle and a computer station.
We show TripAdvisor reviews for new Venere hotels that haven't been reviewed yet
Check Availability at Resort Breckenridge Park Meadows by Ski Country Resorts
Resort Facilities at Breckenridge Park Meadows
- Personal newspapers
- Newspapers
- Concierge
- Luggage room
- Shuttle service from and/or to the airport
- Shuttle service
- Free parking
- Entire property is non-smoking
- Laundry room
- Internet/Email services
- TV Lounge
- Indoor entertainment room
- Billiards / Snooker
- Ski room
- Barbecue
Know before you go
- This property offers transfers from the airport (surcharges may apply). Guests must contact the property with arrival details 48 hours prior to arrival, using the contact information on the booking confirmation.
- A resort fee is included in the total price displayed.
Check-in: between 4 PM and 8 PM.
Check-out: before 10 AM.
The check-in location differs from the property location. To check in, go to Ski Country Resorts
The check-in times for this property vary from month to month. For more details on check-in times, please contact the office using the information on the reservation confirmation received after booking.Guests arriving outside of normal business hours should park behind the office building at 213 N. Main Street and walk up the back steps. There is a drop box on the left which will have an envelope with guest's name on it containing everything needed.
PolicyExtra-person charges may apply and vary depending on hotel policy.
Government-issued photo identification and a credit card are required at check-in for incidental charges.
Special requests are subject to availability upon check-in and may incur additional charges. Special requests cannot be guaranteed.
- The name on the credit card used at check-in to pay for incidentals must be the primary name on the guestroom reservation.
City tax and/or any other fees charged by the hotel
The following fees and deposits are charged by the property at time of service, check-in, or check-out.
- Late check-out fee: USD 25
The above list may not be comprehensive. Fees and deposits may not include tax and are subject to change.
Room Details
Breckenridge Park Meadows by Ski Country Resorts has 30 guest rooms, all featuring DVD players and climate control. For comfort and convenience, each individually furnished and decorated guest room comes with a separate sitting area. Well appointed kitchenettes offer a range of facilities, including refrigerators, stovetops and microwaves, allowing you to save on dining expenses while you travel.
TVs with premium cable channels offer entertainment at the end of a long day. Corporate travelers visiting the Breckenridge area will benefit from free wireless high-speed Internet access as well as complimentary newspapers. Additional comforts include coffee/tea makers.
Private bathrooms are outfitted with shower/tub combinations. Irons/ironing boards and hair dryers can be provided on request.
Accommodation Services
- Mini fridge
- Coffee and tea maker
- Ironing facilities on request
- Hairdryer on request
- Individually controlled air conditioning
- Cooking corner
- DVD player
- Cable TV
- Wireless Internet access
Distances from Resort Breckenridge Park MeadowsRiverwalk Center - 0.4 km / 0.3 mi
Barney Ford House Museum - 0.5 km / 0.3 mi
Edwin Carter Museum - 0.5 km / 0.3 mi
Breckenridge Ski Resort - 1.4 km / 0.9 mi
Breckenridge Golf Club - 5 km / 3.1 mi
Peak 10 - 6.1 km / 3.8 mi
Woodward at Copper - 8.8 km / 5.5 mi
McCullough Gulch Trailhead - 8.8 km / 5.5 mi
Copper Mountain Village - 9.2 km / 5.7 mi
Copper Mountain Ski Resort - 9.2 km / 5.7 mi
Frisco Adventure Park - 10.6 km / 6.6 mi
Frisco Nordic Center - 10.6 km / 6.6 mi
Frisco Historic Park and Museum - 11.3 km / 7 mi
Keystone Conference Center - 15.8 km / 9.8 mi
Keystone Ski Resort - 16.1 km / 10 mi
The preferred airport for Breckenridge Park Meadows by Ski Country Resorts is Denver, CO (DEN-Denver Intl.) - 124.9 km / 77.6 mi.
Distances are calculated in a straight line from the property's location to the point of interest or airport and may not reflect actual travel distance.
Distances are displayed to the nearest 0.1 mile and kilometer.
Transportation services Resort Breckenridge Park Meadows by Ski Country Resorts
- Shuttle service from and/or to the airport
- Shuttle service
- Free parking
We have the accommodation you need, all over the world
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- • Tramore Hotels, Ireland
- • Majorca Hotels, Spain


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After a special IFC screening of "The Cruise," the Oscar-nominated director sat down with Ira Glass to discuss why he felt the urge to create it.Read More »
Timothy "Speed" Levitch is both an unconventional tour guide and a kind of indie film muse. Working on double-decker bus hosting sightseeing tours in his native New York in the '90s, he attracted attention for his unique, philosophical take on the city and its history. He eventually be...Read More »


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94 N. Main Street, Jasper, GA - (706) 253-2457
There seems to always be a perception that government at all levels is chomping at the bit to take away citizen rights whenever possible.
This mis-assumption was turned on its head at a recent meeting hosted by the Jasper Merchants Association, where a handful of business owners, citizens and representatives of the merchants asked the city to do something about various unsightly sites around town.
We would like to second the response of Jasper Mayor John Weaver who said flatly that most of what he was shown in the photographs of shabbiness is on private property and would be best dealt with by private industry.
The Jasper mayor, who has a long track record of getting involved in development issues, made it plain that when it comes to bringing down the mighty hand of government to force a private property owner to do something out of aesthetic concerns, he's against it.
In this case if your business has chipping paint, weeds growing in an unused parking lot and a pile of debris out front, Big Brother is not watching.
And that is how it should be. The rights of private citizens to maintain their property in a manner they see fit (as long as it doesn't affect public safety) is fundamental to our country. You can be pretty sure George Washington didn't go to the Alexandria city council and gripe about the less attractive farmhouses near his Mt. Vernon mansion.
Weaver did say he would pass along the concerns from the meeting to the owners but would not take any action.
The Jasper mayor clearly recognized that private small businesses are the most effective agent of development. Eventually the commercial properties that made the portraits of shame will be bought and put back into use, especially the one in a prime spot near Ingles.
As an example of this process, Weaver told how one persistent real estate professional requested the city condemn the old Greystone apartments, which for many years were an unsurpassed eyesore at the busy intersection of Burnt Mountain Road and Church Street.
The city held out, eventually the property was bought and now Walgreens stands there. Had the city gotten involved, it would have surely created a mess. If the city had outright taken the prime corner lot, the taxpayers of Jasper would have been obligated to pay the owner for it and to either perform or subsidize the demolition of the apartments and their cleanup.
And then what? You have the city owning a great development lot. Sell it? Develop themselves? A park rather than prime commercial potential?
Our support of private industry solutions does not mean we are deaf to the laments of the neighbors of unsightly properties. For commercial owners, we understand that a run-down property hampers most anything you want to do next door.
And in some cases, one unsightly area can set a bad tone for everything further down the street, a problem noted by the Greystone, which sat on a key entrance to town.
But ultimately, it's the owners of the dilapidated properties decision as to when and how to address it. The right of private property owners to maintain their holdings as they choose is as sacrosanct as any rights we have in this country, even to the point that it may impede commerce further down the road. Indisputably we feel the right to private property trumps the right for a favorable business atmosphere.
Furthermore we would caution that imposing building dress codes is a slippery slope. Today you go after discarded junk in front of shops and tomorrow you see government dictating color choices or building materials. In practical and rhetorical arguments, where do you draw the line?
If you attended one of the meetings or read about the county tax rate increase and were left scratching your head, you were not alone. There is a good reason to be perplexed on county spending. Not so much on the should they/shouldn't they/how dare they level, but the practical explanation doesn't quite account for the 6.55 percent increase in property taxes imposed this year.
Through the series of meetings and additional outside reporting by this newspaper, it became clear that nothing is simple with our county's finances and this lack of straightforwardness leads to distrust by the citizens. It also sets up poor decision making by the commissioners and department heads; if it's hard to decipher where everything is going, it's hard to root out waste.
The core problem of getting a handle on the finances of Pickens County goes to the basic timeline of when budgets and tax rates are set. In the defense of the current commissioners, this isn't anything new.
To explain it simply, what the commissioners just approved was a tax rate for 2014, which will (in theory) pay for what we have spent since January 1 and on through the end of the calendar year.
The commissioners are set to open their budget workshops for 2015 this month where they will lay out the spending priorities for next year.
County CFO Faye Harvey has likened the system to "credit card spending," you are always borrowing ahead and paying off what was spent in the past. This malfunctioning time system is abetted by the use of county borrowing in January against what they will collect in the fall.
Many of the critics at public hearings focused on the Tax Anticipation Notes (TAN) where the county borrows in January against future taxes. Rather than the problem itself, we see TANs more as a symptom. The TAN is annual proof that the county squandered previous surpluses and we are sitting with insufficient funds in the savings account of Pickens County. When a new year opens, it's back to the bank.
But even if the county had a comfortable nest egg, the underlying problem of setting budgets and tax rates almost a year apart still circumvents tight financial controls and leaves the whole system a ball of confusion on what is getting paid by which year's taxes.
In Pickens County finances (like many other counties) passing tax rates for what has already been spent and setting budgets for items that commissioners won't have to impose taxes on until months later is a system ripe for overspending.
Theoretically it should not matter when taxes are collected. A government should total up all expenses (add a little bit for cushion) and that is your tax rate.
In reality, when you have a budgeting process almost a year divorced from tax rate approval, there is no sense of imminent impact. Commissioners and their department heads may be tempted to think, "we'll find a way to fund this before tax time arrives."
Or, as happened this year, the county justifies current taxes by future spending. Some of our taxes in 2014 go to "support" needs expected in 2015. We would counter, how do you know you need this support, when the budgets are not set?
One might praise their estimating foresight as looking ahead, but from what we saw this year it was more of a shell game – throwing out a few items we have to pay for next year (not calculate any decreases) and use it to justify higher taxes right now.
The rationale that they needed more taxes this year to pay for stuff next year is a ploy that could go on for infinity – a county will always need something in the next year. It might also be noted that one of the items (a mapping system) isn't required until 2020 and a related technology position might produce savings.
The prospect of re-aligning the county operation to coordinate their tax rate schedule and budgeting schedule is not simple. There are tons of state requirements on setting a digest and tax appeals that must be handled at specified times.
But to get through the smoke and mirrors, which leaves property owners angry and governments with too many ways to claim their hands are tied when it comes to spending cuts, we need to re-align how we do business.
When a fully-loaded lumber truck overturned on Cove Road last week scattering boards all across the asphalt and causing the road to remain closed for most of the day, no one expressed any particular surprise, for a wreck at that spot is nothing unusual.
The general sentiment was "thank goodness no one got hurt…. This time."
Our records don't show any recent fatalities at the Cove, as it's commonly known. But we regularly post notices about the road being closed while emergency crews clear wrecks on the S curves.
The stretch of road causing all the motor vehicle grief is an extremely steep grade with sharp S-curves that, though well-marked, seems to surprise motorists approaching from the east.
From an aesthetic point of view, it's quite impressive to see the road snaking through the cliff above the former marble mines after after crossing Longswamp Creek (very often called Cove Creek).
But from a traffic, motorist point of view, it's sheer lunacy that such a steep and narrow road serves as one of two major east-west traffic arteries for Pickens County (Hwy. 53 being the main one). Cove Road is extremely well used with both Bent Tree and Big Canoe gated communities tied to Jasper by this route.
The road is also the only practical choice for many people as a daily commute. There are few options to detour off the route unless you are really familiar with the backroads of the county and none of those routes are efficient, winding well out of the way.
The traffic woes of Cove Road escalate by the lack of alternatives and the fact that it is difficult to move cars, patients and, as we saw last week, lumber, out of the way to get traffic flowing again in the S-curves.
Commissioner Billy Newton, who was lucky enough to serve as sole commissioner when multi-million dollar development deals seemed to fall out of the sky during the early 2000s, had identified doing something to address the S-curves as a top long-term project.
He had general ideas that a dam could be put across the creek at the bottom and the road straightened by running it along the top of the dam, creating water reserves and fixing the traffic issues at the same time. Nothing came of this and obviously tackling something this large is a multi-year, phenomenally expensive scheme, unlikely to draw support now that the development wave has passed.
When a rockslide occurred in April of 2011 and closed Cove Road for several days of cleanup, one county employee said the entire cliff was unstable and something major needed to be done. Several low concrete barriers were installed at the base that serve little apparent purpose but nothing substantial was ever planned.
And again when a single overturned truck was able to shut down a major thoroughfare for a full day, there were calls for action. Several people opined that the road should not be used for larger truck; while others noted that some GPS and online mapping programs direct you down Cove when approaching from Dawsonville. If we could let the Google maps/Garmin folks know that unsuspecting truck drivers such stick to Highway 53 it would be a start.
We understand that a total reconfiguration of the S-curves is such a large, expensive and complicated project that the county, city of Jasper or state can not just take some bulldozers and start grading. We fully realize that due to the very topography that creates hazard, addressing the Cove is a humongous challenge.
But surely something can be done there to improve the safety -- even if it's not a total reworking. At the very least we would like to see the need formally acknowledged on city, county and state drawing boards.
It seems hard to fathom that a virus in Africa can be potentially dangerous to us here in the United States but Ebola is a real and emergent threat. Whether through the virus itself spreading to our shores or by the collapse of established nations that allow terrorist groups a new stronghold, the outbreak of Ebola in West Africa is on our national security radar screens -- and for a good reason.
More than 5,300 people in Guinea, Liberia, Nigeria, Senegal and Sierra Leone have contracted Ebola since March. To date more than 2,630 have died in the biggest Ebola outbreak on record. The virus kills 90 percent of the people it infects and its outbreaks occur primarily in remote villages in Central and West Africa, near tropical rainforests, according to the World Health Organization. The virus is transmitted to people from wild animals and spreads in the human population through human-to-human transmission. There is no licensed vaccine for Ebola.
President Barack Obama last week announced the United States' plans to expand military and medical resources to combat the outbreak, constructing Ebola treatment centers with 1,700 beds, training 500 medical workers a week and deploying some 3,000 American military personnel - including doctors - to Liberia and Senegal. The Liberian minister said on Sunday the epidemic threatens to entirely "collapse" three states - Liberia, Guinea and Sierra Leone.
Last week the U.S. doctor who contracted the virus and was subsequently healed, Dr. Kent Brantly, testified before a senate committee that the use of our military is legitimate to stop this outbreak. He said: "If we do not do something to stop this outbreak now, it quickly could become a matter of U.S. national security - whether that means a regional war that gives terrorist groups like Boko Haram a foothold in West Africa or the spread of the disease into America."
Liberia was in its 11th year of peace and the Ebola epidemic is striking just as hope was returning to that devastated nation. Only around 40 percent of the country's healthcare facilities are operational and all schools are closed.
Most doctors agree that the risk of anyone in the United States contracting Ebola is very small - you can't catch Ebola just by being in proximity to someone who has the virus; it is not airborne like the flu. While the World Health Organization said it expects 20,000 cases within the next nine months, a group of American scientists said the outbreak could infect hundreds of thousands of people before it is brought under control.
With that many people infected, we could see profound political, economic and security implications. The "ripple effects" the president spoke of include economic and humanitarian disasters that pose a threat to global security if these African countries break down. Terrorist groups could use the virus as a bio-weapon. The current outbreak is occurring near an always volatile region that has seen the rise of different terrorist groups. Boko Haram operates there and is the group that abducted more than 200 girls earlier this year.
According to the Washington Post, the U.S. has invested tens of millions of dollars in vaccine and therapy research over the last decade. And a Department of Defense spokesman, when asked if they worried Ebola would be used as a bio-weapon, replied that "the DOD maintains research interests both for protection against intentional use and natural exposure to many diseases that can impact the health of its personnel around the world, and that concern extends to viruses, such as Ebola."
They should. Back in the 1970s the Soviet Union had a program called VECTOR aimed specifically at researching biotechnology and virology, which is now believed to have had people tasked with creating Ebola and Marburg (a virus similar to Ebola) biological weapons. Funding research into vaccines is a sound protective measure and while we may be doing it out of national security considerations, a vaccine could save lives both here and abroad.
The best way to protect the United States is to stop the outbreak in West Africa.
Thursday night a vivid rainbow hung above JeepFest 2014's home base in the field behind Ingles, providing a charming backdrop to the beginning of an event that would bring 1,300 officially registered Jeeps roaring into the small town of Jasper and hundreds more Jeepers who were on-hand as spectators.
The Monday after four days of trail rides, obstacle courses and car crushes, the red dirt started to wear off roads near the field where cleanup was underway.
Now that the dust has settled we'd like to congratulate the Pickens County Sheriff's Office on a job well done, and take the opportunity to say we're proud of the way our little town pulled together to make the event go off without a hitch.
From the countless number of folks who volunteered to others who rolled out that unmistakable southern-charm to welcome the crowds, Pickens proved that just because the town is small doesn't mean the thinking is small or that things here can't be top-notch.
Not only did JeepFest 2014 raise thousands of dollars for the Georgia Sheriff's Youth Homes, The Joy House and the Pickens Sheriff's Foundation (an organization that was formed after a round of devastating tornadoes here and still offers emergency assistance and scholarships), it brought thousands of tourists into town who ate and slept here, and made being at home feel kind of like traveling.
Progress staff members who volunteered Friday at the JeepFest t-shirt booth made a point to ask where folks were from. One couple drove from New Orleans. Another was from Asheville. A guy from Ft. Lauderdale said he left Tuesday and took over 1,400 miles to tootle around before he eventually wound up in Jasper. Very few people surveyed were from Pickens, and it's exciting to think about people from across the country making our town their destination for a weekend.
Some locals might argue that events like these can be a nuisance and do little more than tie up resources and create traffic jams, especially for people who aren't into Jeeps. One NPR report spotlights Traverse City Michigan, a small town with big events many times each year. Residents there complained to commissioners that they were tired of festival-goers hogging their parks and clogging up their roadways, but Pickens - which boasts just a couple big festivals annually - still has the luxury of viewing festivals as novel and fun.
In the same NPR article Dan McCole, assistant professor and tourism researcher at Michigan State University, says festivals are actually more in line with the way Americans are traveling and vacationing nowadays - shorter weekend trips. Many Jeepsters were from out of town, but close enough that the drive here was painless (Marietta, Alpharetta, Chattanooga).
Our otherwise subdued town came to life and we were given the opportunity to showcase Pickens and see people take pride in our community, like the guys who won the bid to crush the Sheriff's car. All were from Pickens, and going into the bid one of them said he felt like the car crush needed to be done by locals to keep it in the family. Heck yeah. We agree.
So, from the folks who organized the event, to the guys guiding trail rides, to law and emergency personnel who worked the streets to keep things safe, to business owners and everyone else involved, good job on contributing to a great event. For a weekend our little town was on stage, and we think everyone can agree. Pickens nailed it.


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Our full dinner menu has long-loved signature dishes as well as frequently changing short-term seasonal offerings.
A range of affordable dishes from our Saikyo Miso Black Cod to a Berkshire pork cutlet sandwich in a beautiful sunlit restaurant.
Saturday & Sunday, we offer a brunch medley of both western twists & traditional "choshoku" Japanese breakfast.
NYC restaurant week
Our annual return to the New York City restaurant week is different this year in that we are only offering special RW menus for lunch service. Please note that dinner will be limited to our regular menu.
delivery & takeout
EN offers delivery to a large portion of lower Manhattan. Delivery is free but we do have a $25 minimum for lunch and $35 minimum for dinner. Even if outside of our delivery area, please feel free to order takeout for pickup at the restaurant.
click HERE to order via
With a wide selection of small production shochu, carefully selected sakes offered by the glass and original cocktails, EN has something for every mood. Kanpai!
event packages
EN offers an assortment of packages for large parties, including standing hors d'oeuvres, full seated dinner, open bar and sake tasting packages. Please email us at firstname.lastname@example.com or call 212.647.9196 x204 for more information.
EN is pleased to offer offsite catering. For more information on menus and pricing, please email us at firstname.lastname@example.com or call 212.647.9196 x204.
435 Hudson Street (at Leroy)
New York, NY 10014
tel 212 647 9196
monday thru friday 12:00 PM - 2:30 PM
saturday & sunday 11:00 AM - 2:30 PM
sunday thru thursday 5:30 PM - 10:30 PM
friday & saturday 5:30 PM - 11:30 PM
(bar opens at 5:00)


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Award-winning barbershop chorus reinterprets a collection of The Beatles' greatest hits with their gilded pipes
Multiple Locations
$15 $10
Tricky Dick & the Cover Ups at House of Blues Cleveland on Friday, April 10 (Up to 50% Off)
Tricky Dick & the Cover Ups
House of Blues Cleveland
Energized party band inspires dancing with a non-stop mashup of pop, EDM, and rap hits backed by an awe-inspiring light show
View Deal
Brunch, Bloodys, and Breweries Bus Tour to Platform Beer Co. and Brick and Barrel
Brunch and Brewery Tour
Following bloody marys and brunch, ride a party bus to Platform Beer Co. and Brick and Barrel for tours and samples
$13.99 for $20 Worth of Movie Tickets and Concessions at Cleveland Cinemas and more from Dealflicks
Guests enjoy $20 worth of Dealbucks, which they can use to buy movie tickets and concessions at multiple theaters on Dealflicks.com
The Righteous Brothers' Bill Medley on Saturday, April 11 (Up to 54% Off)
The Righteous Brothers' Bill Medley
Hard Rock Rocksino Northfield Park Hard Rock Live
The famed baritone behind "You've Lost That Lovin' Feelin'" and "(I've Had) The Time of My Life" shares decades of unchained melodies
Wine Tasting and Small Plate for Two at Secret Cellar (Up to 48% Off). Two Options Available.
Secret Cellar
Sample eight wines along with a small plate of gourmet snacks
Standup Comedy at Funny Stop Comedy Club (Up to 57% Off)
Funny Stop Comedy Club
Seven-time Cleveland Hot List-topping comedy club hosts headlining comedians in weeknight and weekend showcases
Cinderella's Tom Keifer with guitarist Billy Morris at Akron Civic Theatre on 6/18 at 7:30 p.m. (Up to 50%Off)
Tom Keifer w/ former Warrant guitarist Billy Morris and Joey D from Liquid
Akron Civic Theatre
Joined by Warrant's guitarist and Liquid's lead singer, Cinderella's frontman earns new fans with his bluesy hard rock
University Of Akron Steel Drum Band at E.J. Thomas Hall, The University of Akron on April 18 (Up to 49% Off)
The University Of Akron Steel Drum Band
E.J. Thomas Hall, The University of Akron
Collegiate steel drum ensemble delivers a set of upbeat and summery Caribbean tunes
Hookah with Bubbles and Drinks at Karma Kafe (Up to 72% Off). Four Options Available.
Karma Kafe
Downtown Akron
More than 30 hookah flavors include lime, mango, cinnamon spice, pink lemonade, and mint chocolate
Kidz Bop Kids: Make Some Noise Tour at Packard Music Hall on Friday, June 19, at 7 p.m. (Up to 48% Off)
Kidz Bop
Packard Music Hall
Stars of the longstanding series put on a live show that might feature covers of songs by Meghan Trainor, Charli XCX, and Ariana Grande
$12 for a Wine Tasting and Cheese Board for Two at Laurello Vineyards ($24 Value)
Laurello Vineyards
Pair wine tastings with two premium cheeses, a cranberry-feta spread, fig preserves, candied walnuts, and crackers
$16 for a Wine Tasting for Two with Glasses, Desserts, and Bottle of Wine at D&D Smith Winery
D&D Smith Winery
Sample your choice of about 24 varieties at a winery located in a quaint home dating to 1870; take home a bottle of your favorite wine
Two Beer Flights at Lavery Brewing Company (Up to 50% Off). Two Options Available.
Lavery Brewing Company
Sample year-round and seasonal beers brewed in small batches, including IPAs, an imperial red ale, and a black saison
Tour Package for Two or Four at Quai du Vin Estate Winery and Railway City Brewing Company (Up to 54% Off)
Quai du Vin Estate Winery and Railway City Brewing Company
Visitors tour winemaking and beer-brewing facilities, taste the products, and use gift cards toward bottles and gifts
Brewery-Tour Package for Two or Four at Railway City Brewing Company (Up to 55% Value)
Railway City Brewing Company
Brewmasters turn Ontario-grown grains and hops into small-batch craft beers, such as the Dead Elephant IPA and Iron Spike blond ale
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From NBC's Today Show this morning- Duggars visit fertility doctor: 'We would love' more children, parents of 19 say "We would love more children if God saw fit to give us more, I just want to make sure that I am ready to catch a baby if that would happen," Michelle Duggar says as she goes to see Dr. Paul Wendel, an OB-GYN in Little Rock, Arkansas, who specializes in high-risk pregnancies. … [Read more...]
Quoting Quiverfull: Michelle Duggar Doesn't Trust in God For the Size of Her Family After All?
News: Highest Divorce Rates?
by Christine Wicker at Adherents.com - Dumbfounded by Divorce A study saying that born-again Christians divorce more often than non-Christians has raised eyebrows, sowed confusion, even brought on a little holy anger. So much, in fact, that the study's author, evangelical George Barna, put out a special letter to "our partners in ministry" trying to calm their fury and let his fellow believers know that he was standing by his stats no matter how distasteful they might be. … [Read more...]
Seven Phases of a Godly (Gothard) Courtship
by Libby Anne cross posted from her blog Love, Joy, FeminismSo I'm going to dip my toes into Bill Gothard's Advanced Seminar Textbook once again, this time looking at a section titled "Seven Phases of a Godly Courtship" (pages 160—164). This, too, is a teaching I am unfamiliar with. Yes, I was taught courtship, but without specific "phases." … [Read more...]
News: Did the Medical Care Received Equal an Abortion or Birth Control?
Just like many of you dear readers we have been following Zsuzsanna Anderson, the wife of Arizona pastor Steven L. Anderson at her blog, Are They All Yours!!, and watching her recent struggles with a high risk pregnancy. Thankfully the medical treatment she received for Twin to Twin Transfusion Syndrome helped her deliver a normal healthy baby boy. … [Read more...]
Gender Transition: Two Years Later
by Melissa from her blog Permission to LiveA guest post written by my wife HaleyLast week marked the two year anniversary of when I started hormone replacement therapy for transitioning my physical body to female. My transition didn't start with hormones, due to challenges and an involved process to get access to hormones, many other transition milestones had already happened before that day. I was already full time and out to the world as transgender in March 2012. I had changed my name legally the previous October. … [Read more...]
Quoting Quiverfull: Socialization Isn't Important?
by Matt Walsh at The Matt Walsh Blog - Behold: the two absolutely worst arguments against homeschooling I'll only say that you chose a pretty strange analogy to prove your point. You can't teach a child to swim without bringing him to a pool? I agree. But do you bring a child to the pool, drop him there with a thousand other kids, then come back 6 hours later, and repeat that process every day, five days a week, for the next 12 to 13 years? Or do you bring him to the pool, hang out with him, maybe even get in the water and play some Marco Polo, and then leave with him after a couple of hours? … [Read more...]
Quoting Quiverfull: God Wants Daughters In Waiting To Wait At Home?
by Jenny McGinnis at Above Rubies - Daughters in Waiting: Finished School? What Now? Upon reaching the age of 18 and officially graduating from our family home school, I immediately met with very intense pressure from friends, teachers, and others to pursue a profession, attend college and even move out and get a "place of my own." Many people assured me this would enable me to become a successful, independent career woman. … [Read more...]
Quoting Quiverfull: Motherhood is Servanthood?
by Nancy Campbell at Above Rubies - To Serve or Not to Serve I have been thinking about our great role of "serving" in motherhood. As a young mother I remember feeling "I'm just a jolly servant around this place." I was still filled with selfishness, and although I loved my children and loved motherhood, I still wondered why I had to be the servant. … [Read more...]
Book Review – 13:24: A Story of Faith and Obsession by M. Dolon Hickmon
by Suzanne Titkemeyer cross posted from her blog Seeking The LightBook Review: 13:24: A Story of Faith and Obsession by M. Dolon HickmonA good lesson for me is to never judge a book by its cover, literally.Before I start my review I have to confess that when '13:24' first came to my attention I had no interest in reading it, not even with Vyckie Garrison of NLQ's recommendation. I took one look at the cover, saw the shaggy-haired heavy metal lead singer and the animal skull above and decided this book wasn't something I'd be interested in. I knew there would be descriptions of physical and spiritual abuse and figured I was not going there again because this book would trigger me … [Read more...]
Patriarchy in Homeschool Culture
by Samantha Field cross posted from her blog Defeating the Dragons I grew up in a subculture of evangelical Christianity that's known as "Christian Patriarchy," which is what the people who preach and teach this "lifestyle" un-ironically call it. I was also peripherally a part of the Quiverful and Stay-at-Home-Daughters movements, which are all separate things. A family can be Quiverful without preaching Christian Patriarchy or requiring daughters to remain at home until marriage, for example. … [Read more...]


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Written on: 16/07/2014 by veroly (1 review written)
Very impressed overall, had to wait couple of days for appointment but could have put claim in online to save that. Dealt with within 10 minutes, no pressured questions or assumption that I was trying to make a false claim. The guy was polite and informative. I had to pay an excess fee but considering I've had the insurance free for 18 months I suppose it balances out. Good service and lucky I had the cover after my 'waterproof Sony' went for a swim and died!
As rated by real users
" Easy Peasy " Read More
" Excellent service " Read More
" Very impressed " Read More
" AVOID COVERCLOUD!! " Read More
Written by adamg1977
" Relatively happy " Read More


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Have been going there for years and every time we go to Wildwood we go to Bandanas once for dinner. they have a nice varied dinner. Lots to chose from. Also their ice cream is the best around!!!
Have been going there for years and every time we go to Wildwood we go to Bandanas once for dinner. they have a nice varied dinner. Lots to chose from. Also their ice cream is the best around!!!
Although I am not a fan of Mexican food, the food at Bandanas is really good. It is a very enjoyable place to eat. It is very popular in Wildwood so I suggest you go for an early meal or just stop by on your evening walk and get a delicious ice cream treat.
The food was authentic. My daughter loved the fish tacos...very fresh! This place also had excellent ice cream! Try the peanut butter, it's to die for:). And the prices were very reasonable!
My husband and I were looking for a restaurant that was in walking distance from the condo we rent during the summer. We went for a walk and found Bandanas. We returned that night with friends and enjoyed an excellent meal at this BYOB. Service was quick and very pleasant. Prices were very reasonable.
Don't eat here if you are celiac. They are not aware of the dangers of cross contamination. They served my daughter's gluten free salad in a taco shell with wheat. They suggested that I just remove the salad from the shell. They also fry their chips with other items that contain gluten but don't disclose that. They are overpriced and... More
The food is always very good, fresh and plentiful. You may have a wait but they have call ahead seating where they put your name on the list 15 minutes before you plan to arrive. We go to Bandanas every time we visit Wildwood. It is one of our favorites.
My husband and I went here for dinner. No alcohol served at this restaurant which was fine but their ice tea was awful! Yuk! We got appetizer awful! We ordered dinner! Awful! Price was so over priced for mexican food! Awful! Don't waste your time or money going here!
This review leaves our staff dismayed and bewildered. At Bandanas we strive to maintain the highest standards of guest satisfaction. Although we have no idea what it was about your dining experience that you disliked, (except the iced tea), we wish we would have had the opportunity to serve you better. Our knowledgeable staff can answer questions about ingredients and... More
Have been going there for years and every time we go to Wildwood we go to Bandanas once for dinner. they have a nice varied dinner. Lots to chose from. Also their ice cream is the best around!!!
I think the lady was the owner, but I am not really sure, however she was rude to my wife as we walked in. The attitude that we got was that we were bothering her. In a good mood we let it slide and she seated us. We ordered our food and instead of a beef dish I received a... More
Oh my.....I hope it wasn't me who gave you a bad first impression of Bandanas! I mostly stay in the back, but every once in a while they let me out into the dining room, and, I must admit, our great hostess staff does a much better job of greeting guests than me! About your food....I assume you told your... More
Chips and salsa were delicious. We got 2 different soft shell tacos and there was nothing special about them. The meat was drowned by some sort of sauce. Waiter could have been more interested in us than he was. Expect better food and service from a shore/resort restaurant.
Although I'm not a huge fan of Mexican food, we tried Bandanas for dinner because they do have a varied menu. I ordered pulled pork sandwich which was very good. The guacamole dip was excellent and everyone was happy with their choices. Of course the ice cream sundaes were awesome and they offer a 'Lite' sundae in a smaller size... More
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Georgia Police: 10-Year-Old's Body Found In Trash Can
Posted: 11/02/2013 - The father and stepmother of a 10-year-old girl whose body was found in a trash can at a metro Atlanta apartment complex have been charged with murder.
Posted: 11/02/2013 - The father and stepmother of a 10-year-old girl whose body was found in a trash can at a metro Atlanta apartment complex have been charged with murder.
Posted: 11/02/2013 - It's time to fall back.
Posted: 11/02/2013 - Honda is recalling 344,000 Odyssey minivans of the 2007-2008 model years to fix a problem that can cause the vehicle to brake suddenly, but because the fix won't be available until next spring, owners are getting specific instructions on how to start and drive their vehicles to avoid a problem.
Posted: 11/02/2013 - A Michigan gem merchant who claims he tipped the FBI to the location of Osama bin Laden's secret compound in Pakistan eight years before his killing has hired a high-powered Chicago law firm to help him seek the $25 million reward offered for the terrorist's capture.
Updated: 11/02/2013 - Federal prosecutors have filed murder charges against the suspected gunman in the deadly shooting at Los Angeles International Airport.
Posted: 11/01/2013 - The FAA has determined that all airlines can safely expand passenger use of Portable Electronic Devices during all phases of flight.
Posted: 10/31/2013 - President Barack Obama's seemingly hands-off management style is raising fresh questions and concerns that could upend his second-term legacy.
Posted: 10/31/2013 - A majority of Americans – 52 percent – believe the health care law needs either a major overhaul or to be completely eliminated, a new NBC News/Wall Street Journal poll finds.
Posted: 10/31/2013 - A new bill was introduced in the U.S. House of Representatives to try and keep flood insurance rates from going out of control here in the east. The Insurance Affordability Act, cosigned by Congressman Walter Jones, could delay increases.
Posted: 10/30/2013 - Amazon has launched a new website for its online store that will donate a fraction of shoppers' purchase amounts to charity.
Posted: 10/30/2013 - A 40-year-old man will earn the dubious distinction as Milwaukee County, Wisconsin's 1,000th repeat offender busted since tougher DUI laws went into effect in 2010.
Posted: 10/30/2013 - The L.E.D stick baby costume that went viral a few weeks ago isn't for sale until 2014, but there are other things parents can do to keep children visible as they roam the street in search of treats.
Updated: 10/30/2013 - Health and Human Services Secretary Kathleen Sebelius says she's sorry consumers have wasted so much time dealing with technical problems on the Obama administration's health insurance website.
Updated: 10/29/2013 - The decision to release the 26 has triggered anguish and anger in Israel, where many view the men as terrorists who have committed grisly crimes against Israelis. Jubilant celebrations kicked off in the West Bank and the Gaza Strip where the prisoners are seen as heroes.
Posted: 10/29/2013 - Team USA will now wear the Made in the USA label.
Posted: 10/29/2013 - Landing gear on a small plane collapses causing the plane to make hard landing.
Updated: 10/29/2013 - With website woes ongoing, the Obama administration Monday granted a six-week extension until March 31 for Americans to sign up for coverage next year and avoid new tax penalties under the president's health care overhaul law.
Posted: 10/28/2013 - The United States could lose access to an important law enforcement tool used to track terrorist money flows, German officials said Monday, as Europe weighed a response to allegations that the Americans spied on their closest European allies.
Posted: 10/28/2013 - Penn State says it is paying $59.7 million to 26 young men over claims of child sexual abuse at the hands of former assistant football coach Jerry Sandusky.
Posted: 10/28/2013 - The American Academy of Pediatrics has new advice many kids will find hard to swallow: It wants limits on tweeting, texting and other social media.
Posted: 10/28/2013 - A British man has been arrested and charged with hacking into computer systems of the U.S. Army, NASA and other federal agencies.
Updated: 10/29/2013 - It's a trend taking off around the country, people "paying it backward" at drive-thru windows. But customers at this Texas fast-food restaurant took it to a whole new level.
Posted: 10/28/2013 - A bus carrying Kentucky high school students on a field trip to Tennessee burst into flames Friday afternoon.
Updated: 10/28/2013 - The former doctor convicted of causing Michael Jackson's death has been released from jail.
Posted: 10/27/2013 - A Chinese immigrant was arrested Sunday on five counts of murder in the deaths of his cousin's wife and her four children in a stabbing rampage in their Brooklyn home.


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2011 MINI COOPER CLUBMAN S Contact for Price
- Contact for Price
- Mileage 49,137 Miles
- Mileage 49,137 Miles
- Color Gray
- Engine 4 Cyl
- Location Medford, OR
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Russell Korobkin's Negotiation and Conflict Resolution Colloquium presents Professor Barbara Walter of U.C. San Diego.
A conversation with Gary Bass, professor of politics and international affairs at Princeton University.
Cameron Munter is the former United States Ambassador to Pakistan, and currently a Professor of
Michael McFaul, former U.S. Ambassador to the Russian Federation, U.S. Department of State
11353 Bunche Hall
Box 951487
Los Angeles, CA 90095-1487
Campus Mail Code: 148703
Tel: (310) 206-6365
Fax: (310) 206-3555
Email: email@example.com


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Currently unavailable for purchase
He is plotting to take over the world.
cat, cute, kitten, loki, pet, silver, tabby
Lights, Camera, Still Shots, and Action
"Do you see what I see?"
Art through a camera's lens: A wide range of subjects and methods of photography, and lighting. From panoramic shots, to macro photography. Digital and Traditional art.
He's really cute, Sandra.
And he knows it. :)
Darling cat love it, just love it…
Thank you. It was just such a lucky shot.
– Sandra Chung
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