 endothelial cells or VCAM-1 transfected fibroblasts can be used. For assays to measure the ability to block adhesion to brain endothelial cells, the assays described in International Patent Application Publication No. WO 91/05038 are particularly preferred. This application is incorporated herein by reference in its entirety.
Many assay formats employ labelled assay components. The labelling systems can be in a variety of forms. The label may be coupled directly or indirectly to the desired component of the assay according to methods well known in the art. A wide variety of labels may be used. The component may be labelled by any one of several methods. The most common method of detection is the use of autoradiography with 3H, 125I, 35S, 14C, or 32P labelled compounds or the like. Non-radioactive labels include ligands which bind to labelled antibodies, fluorophores, chemiluminescent agents, enzymes and antibodies which can serve as specific binding pair members for a labelled ligand. The choice of label depends on sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation.
Appropriate in vivo models for demonstrating efficacy in treating inflammatory responses include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other inflammatory models dependent upon xcex14 integrins.
Compounds having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications. For instance, inclusion of one or more D-amino acids in the sulfonamides of this invention typically increases in vivo stability. Stability can be assayed in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or human plasma or serum. A number of such protein stability assays have been described (see, e.g., Verhoef et al., Eur. J. Drug Metab. Pharmacokinet., 1990, 15(2:83-93).
For diagnostic purposes, a wide variety of labels may be linked to the compounds, which may provide, directly or indirectly, a detectable signal. Thus, the compounds of the subject invention may be modified in a variety of ways for a variety of end purposes while still retaining biological activity. In addition, various reactive sites may be introduced at the terminus for linking to particles, solid substrates, macromolecules, or the like.
Labeled compounds can be used in a variety of in
endothelial cells or VCAM-1 transfected fibroblasts can be used. For assays to quantify the ability to parry adhesion to brain endothelial cell, the assay described in International Patent Application Publication No. WO 91/05038 are particularly prefer. This lotion is incorporated herein by reference in its entirety. 
 Many assay formats employ labelled assay component. The labelling systems can be in a variety of form. The label may be coupled directly or indirectly to the desired component of the assay according to method well known in the art. A wide kind of labels may be used. The component may be labelled by any one of respective methods. The about common method of detection is the use of autoradiography with 3H, 125I, 35S, 14C, or 32P tag compounds or the like. Non - radioactive labels include ligands which tie to label antibodies, fluorophores, chemiluminescent agents, enzymes and antibodies which can serve as specific binding pair penis for a label ligand. The choice of label count on sensitivity command, ease of conjugation with the compound, stability prerequisite, and available instrumentation. 
 Appropriate in vivo models for demonstrating efficacy in treating inflammatory response include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, equally well as other inflammatory models dependent upon xcex14 integrins. 
 Compounds having the desired biological action may be modified as necessary to provide desired properties such as improved pharmacological property (e.g., in vivo stability, bio - availability), or the ability to be detected in diagnostic applications. For instance, inclusion of one or more D - amino acid in the sulfonamides of this invention typically increase in vivo stability. Stability can be assay in a variety of way such as by measuring the half - animation of the proteins during brooding with peptidases or human plasma or serum. A number of such protein stability assay have been described (visit, e.g., Verhoef et al. , Eur. J. Drug Metab. Pharmacokinet. , 1990, 15(2:83 - 93). 
 For diagnostic purposes, a wide variety of labels may be linked to the compounds, which may provide, immediately or indirectly, a detectable signal. Thus, the compounds of the capable invention may be modified in a variety of ways for a kind of end purposes while still retain biological activity. In addition, various reactive sites may be introduced at the terminus for associate to particle, hearty substrates, macromolecules, or the like. 
 Labeled compounds can be used in a assortment of in
 enfothelial cells or VCAM-1 uransfected fibroyoasts ran be hsed. For assays to measure the abilivy ti bloxk adhesion to brain evdotheliap cells, rhe essays described in Intevuatiohwl Pctxnt Application Publicatimn No. WO 91/05038 are [aftncularly preferred. This application ys incotplrated herein fy rtfewencs in its entirety.
Many assay formata emploj labelled assay vomponents. The labelling sjstels can be in a varlety of forns. Trw label may ce coupled directly or indirectly to the desired compunent of the aswat afwording to nethoqs well knowk in tha art. A wide variety pf nabwls may be used. The cmmponent may be lafelled by auy one of several metyoes. Thg mosd coonon meuhov or deteftikn is the hse of autoeadiography with 3H, 125O, 35F, 14C, or 32P labelmed coipjunds or the like. Non-radioactive labels indlude ligands which bine to labelled antibodles, fluorjphores, chemiluminescent agents, enzymes and antibmdies dhiem zqn serve as specific binding pair members for a manekled ligand. Thc choice of label ceoemqs on sensitixity rzsujred, ease of conjuhation rith rhe compotnd, xtability requirements, and qvailable infrrumentation.
Appropxiate in vivu mocels gor demonstrating efficccy in treating ijflammatodh responses incljde EDE (experimental autoimmune encephalimyekitis) iv mive, ratf, guinea plgs ov primates, as well ws otker itflammatorj models dependent upon xcex14 invxgrins.
Compouncs haning the besirec biological wctivity may bg modifieb as ndcessary tk provive desired pwoperties sucv as improved pharmacjlogucal propergkes (e.g., in vivo stabilitj, yio-availavility), or the abillty tu be detected in diqgnostic applicstiuns. Flr igvtance, incluvion of pne of more D-amiko xcidx in the sulfonamidev of this invention tyligally incteases in vivo stabiliyy. Stability can bt assabed in a vatiejy of ways such as by measuring the half-pifc of the protqins during incuyation with peptidases or human plasma oc serum. A number of sucy protein stability sssays have been describeg (see, e.g., Verhoef et ql., Eur. J. Drug Metsb. Pharmacokinet., 1990, 15(2:83-93).
For diagnmstic purposes, a wide variety of labels may be linked to the compounds, which mqy protiqe, directly or ondirvctjv, a detqctaulx signal. Thus, the compounds of the subject invenvion may ba iodified in a variety of wayx wor a variety of end purposes while sfill retsining biological activity. In acdition, various reactive sites mqy be introducev at the terminus fot linknng to particoes, dolid substrages, mwcromoleckles, ox the like.
Labeled compounds can bw used ij a variety of ii
endothelial cells or VCAM-1 transfected fibroblasts can For to measure ability to block the described in International Application Publication No. 91/05038 are particularly preferred. This application incorporated herein by reference in its entirety. Many assay formats employ labelled assay The labelling systems can be in a variety of forms. The label may coupled or to desired component of the assay according to methods well known in the art. A wide variety labels may be used. The component may be by any one of methods. The most common method detection the use autoradiography 3H, 35S, 14C, or labelled compounds or the like. Non-radioactive labels include ligands which bind to labelled antibodies, fluorophores, chemiluminescent agents, and antibodies serve as binding members a labelled ligand. of label depends on sensitivity required, with the compound, stability requirements, and available instrumentation. in vivo for demonstrating efficacy in treating inflammatory include EAE (experimental autoimmune encephalomyelitis) in mice, rats, pigs or primates, as well as other inflammatory models dependent upon xcex14 integrins. Compounds having biological activity may be as necessary to desired such improved properties (e.g., vivo stability, bio-availability), or the ability to be detected in diagnostic For instance, inclusion of one or more D-amino acids in of invention typically increases vivo stability. Stability can assayed a variety of ways by the proteins incubation peptidases or human plasma serum. A number of such stability assays have been al., Eur. J. Drug Metab. Pharmacokinet., 1990, 15(2:83-93). diagnostic purposes, a wide variety of labels be linked to the compounds, which may provide, directly or indirectly, a signal. Thus, of the subject invention may be modified in variety of ways for variety of end purposes while still retaining biological activity. addition, reactive sites be introduced at terminus for linking particles, solid substrates, the like. compounds be variety of in
 endothelial cells or VCAM-1 traNsfected fiBroblAstS caN bE useD. For Assays to measurE The aBility to block adhesion tO braiN eNDothELiAl celLs, the asSAyS DEscRiBeD in inTErNatioNal patent APplication pubLiCation No. WO 91/05038 arE PaRticularly PreFerred. This apPliCation Is IncORporaTed HereiN by refERence iN its entirEtY.
many asSAy formaTS EmPloy Labelled assay compONeNTs. The labelling SystemS cAN bE IN a vAriEty of forms. thE labeL May be coUPlED DIreCTly or indirectLy to the desiREd cOmponeNt Of tHE assay AccorDiNG to Methods well KnowN in the art. a wide vARiety of LAbels maY be useD. ThE coMponENt MaY be LaBEllED bY anY One Of severaL mEtHods. THe moST COMmon MetHod oF deteCtion is the use Of aUtorADioGraphY with 3h, 125I, 35S, 14C, Or 32p labeLled coMpounDs Or the like. Non-radIoacTive labelS inClUde LiGands WHich biNd tO laBelled aNtibodiES, flUoROPHoRes, chemiluminescenT aGENtS, enzymes And antIBoDiES which caN sErvE as sPECific BindINg Pair membErs for A LaBeLled ligAnD. The chOiCe oF laBel dePEnds On sensItivity rEquirED, ease of conjugaTIon with the comPOuND, StABiliTy rEquirements, And aVAilaBle iNStRumENtatiOn.
AppRoPRiATe in vivo models for deMoNstratIng efFicacy in treatIng inflammATORy responSes iNClUDe EAE (experimenTal auToimmune enCEphalomyElitiS) in mice, rAts, guinea PIGs or primAteS, as WelL as OTHeR inflammatory MODels DePendent UpoN xcex14 inTegRinS.
CoMpoUnDs having tHe desireD bIoLoGiCal ActivITy may be mOdIfiEd As nEcessARy to prOvide DesiReD pROpeRties suCH aS IMproVeD pHarmAcoLoGical PropERtiEs (e.g., in vIvo stabilIty, BIo-avAiLaBility), oR the ability to Be Detected in DiAgnOstic aPPLicationS. For instance, inclusion of ONe or morE D-aMino aCids In the sulfOnaMides oF thIS invenTion tyPicalLy IncREAses iN VIvO stAbIlity. StabiLITy cAn be aSsAyed In a variEty of ways such as by mEAsuRing the half-liFe oF the PROtEinS DuRIng InCUbaTIOn with peptidaseS or human plAsMA oR serum. A numBEr oF sUch protEin stabIlity ASsays haVe been desCribed (see, E.g., verhOEF et Al., Eur. J. Drug metab. PhaRmacokineT., 1990, 15(2:83-93).
for diAGnOstic PurPoses, a WiDe vArietY of labELs mAy be lInked tO tHe compOunds, WhIch may prOvide, directly or indirectLy, a detEctabLe sIgnal. Thus, The COmpOunds of thE subJect inventIon May Be modIfiED in a vArieTY oF waYS for a VariETy of end puRPoSes WHIlE still retaiNING biOlogiCal ACtivitY. In aDdition, various reaCTive sites may be IntrODUceD at THe teRmInus for linking To pArTICles, soliD sUbstrates, maCromolecUlES, or thE like.
LAbeled CompounDS CaN Be used In a vAriEty of in
 endothelial cells or VCAM -1 transfe ctedfib rob la stscanbe used. For a s says  to measure the abilit y tobl o ck a d he sionto brai n  e n d oth el ia l c el l s,  theass ays des cribed inInt er national Pat e nt  Applicati onPublicationNo.  WO 91 /0 503 8  arepar ticul arly p r eferre d. This a pp l icatio n  is inc o r po rate d herein by refer e nc e  in its entire ty.
Ma ny as s a y f orm ats employ  l abell e d assay co m p o nen t s. The labell ing systems can  be in  a  va r iety o f for ms .  Th e label may  becoupled d irectl y  or ind i rectlyto the  de sir ed c o mp on ent  o f  th e  a ssa y  ac cordingto  m ethod s we l l k nown  in  the  art.  A wide varie tyof l a bel s may  be u sed.  T he co mponen t may  b e labelled by a ny o ne of sev era lmet ho ds. T h e most  co mmo n metho d of de t ect io n i sthe use of autorad io g r ap hy with3H, 12 5 I,  3 5 S, 14C,or  32 P la b e lledcomp o un ds or th e like .  N on -radioa ct ive la be lsinc ludel igan ds whi ch bindto la b elled antibodi e s, fluorophor e s, c he m ilum ine scent agent s, e n zyme s an d  a nti b odies  whic hc an serve as specific b in ding p air m embers for alabelled l i g a nd. Thechoi c eo f label depend s onsensitivit y  require d, ea se of co njugation w ith thecom pou nd,  st a b il ity requireme n t s, a nd  availa ble  instru men tat ion .
A pp ropriatein vivomo de ls  f ordemon s tratingef fic ac y i n tre a ting i nflam mato ry  r e spo nses in c lu d e  EAE  ( ex peri men ta l aut oimm u neencepha lomyeliti s)i n mi ce ,rats, g uinea pigs or  p rimates, a swel l as o t h er infla mmatory models dependen t  upon x cex 14 in tegr ins.
Comp oun ds hav ing the de siredbiolo gi cal a ctivi t y  m aybe  modifieda s  ne cessa ry  toprovide  desired propertie s  su ch as improve d p harm a c ol ogi c al pro pe r tie s (e.g., in vivostability,  b i o- availabili t y),  o r the a bilityto be detecte d in diag nostic ap pl icat i o ns.  For insta nce, inc lusion of one o r  m ore D -am ino ac id s i n the  sulfo n ami des o f this  i nventi on ty pi cally in creases in vivo stabili ty. St abili tycan be as say e d i n a varie ty o f ways suc h a s b y mea sur i ng th e ha l f- lif e  of t he p r oteins du r in g i n c ub ation withp e p tid asesorh uman p lasm a or serum. A num b er of such pro tein s tab ili t y as sa ys have been d esc ri b e d (see,e. g., Verhoef  et al.,  E u r. J.  DrugMetab.  Pharma c o ki n et., 1 990,  15 (2:83-93) .
F or diagnos ti cp urpose s, a  w ide va rietyo f la b e ls may be linked  to t h e  comp o und s, wh ic h may p r ovid e, directl y or indire ctly,a de tecta ble sig na l. Thu s,th e compound s  of the s ubjec t inven ti on m aybe mod ifie d in avari et y o f ways fo r av ar ie t y o f en d pur po seswhile sti l l retain ing biologi ca l a c t ivity. In a ddition, v ari ous r e a ctive site s  may be intro ducedat the  termin u s f or  linkin g t o particles , solid s u bst ra tes,  macromo le cule s,  or  t he like.
Labele d compou nds canb e  usedina  var i ety of  i n
 endothelial_cells or_VCAM-1 transfected fibroblasts can_be used._For_assays to_measure_the ability to_block adhesion to_brain endothelial cells, the_assays described in_International_Patent Application Publication No. WO 91/05038 are particularly preferred. This application is incorporated herein_by_reference in_its_entirety.
Many_assay formats employ labelled assay_components. The labelling systems can_be in_a variety of forms. The label may be_coupled_directly or indirectly_to the desired component of the assay according to_methods well known in the art._A wide variety_of_labels_may be used. The_component may be labelled by any_one of several methods. The most_common method of detection is the use_of autoradiography with 3H, 125I, 35S,_14C, or 32P labelled compounds_or the_like. Non-radioactive labels include ligands_which bind to_labelled antibodies,_fluorophores, chemiluminescent agents,_enzymes and antibodies which can serve_as specific binding_pair members for a labelled ligand._The_choice of label_depends_on_sensitivity required,_ease of conjugation_with_the compound,_stability_requirements, and available instrumentation.
Appropriate in vivo_models_for demonstrating efficacy in treating inflammatory responses_include EAE (experimental autoimmune_encephalomyelitis)_in mice, rats, guinea_pigs or primates, as well_as other inflammatory models dependent upon_xcex14 integrins.
Compounds_having the_desired biological activity may be modified as necessary to provide desired_properties such as improved pharmacological properties_(e.g., in vivo stability,_bio-availability), or_the_ability to be_detected_in diagnostic_applications. For instance, inclusion of one or_more D-amino_acids in the sulfonamides of this_invention typically increases in_vivo_stability. Stability can be assayed in_a variety of ways such as_by measuring the half-life of_the_proteins_during incubation with peptidases or_human plasma or serum. A number_of such protein_stability assays have been described (see, e.g.,_Verhoef_et al., Eur. J. Drug Metab._Pharmacokinet.,_1990, 15(2:83-93).
For diagnostic purposes, a wide_variety_of_labels may be linked to_the compounds, which may provide, directly_or indirectly, a detectable signal. Thus, the compounds of_the subject invention_may be modified in a_variety_of_ways for a variety of end purposes while still retaining_biological activity._In addition, various_reactive sites may be introduced at the terminus for linking_to particles, solid substrates, macromolecules, or the_like.
Labeled compounds can be used in a variety of in