 also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) and RK, was isolated from murine pre-B cells that were transfected with the lipopolysaccharide (LPS) receptor, CD14, and induced with LPS. p38 has since been isolated and sequenced, as has the cDNA encoding it in humans and mouse. Activation of p38 has been observed in cells stimulated by stress, such as treatment of lipopolysaccharides (LPS), UV, anisomycin, or osmotic shock, and by cytokines, such as IL-1 and TNF.
Inhibition of p38 kinase leads to a blockade on the production of both IL-1 and TNF. IL-1 and TNF stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8 and have been implicated in acute and chronic inflammatory diseases and in post-menopausal osteoporosis [R. B. Kimble et al., Endocrinol., 136, pp. 3054-61 (1995)].
Based upon this finding, it is believed that p38, along with other MAPKs, have a role in mediating cellular response to inflammatory stimuli, such as leukocyte accumulation, macrophage/monocyte activation, tissue resorption, fever, acute phase responses and neutrophilia. In addition, MAPKs, such as p38, have been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and neurodegenerative disorders. Inhibitors of p38 have also been implicated in the area of pain management through inhibition of prostaglandin endoperoxide synthase-2 induction. Other diseases associated with IL-1, IL-6, IL-8 or TNF overproduction are set forth in WO 96/21654.
Others have already begun trying to develop drugs that specifically inhibit MAPKs. For example, PCT publication WO 95/31451 describes pyrazole compounds that inhibit MAPKs, and, in particular, p38. However, the efficacy of these inhibitors in vivo is still being investigated.
Other p38 inhibitors have been produced, including those described in WO 98/27098, WO 99/00357, WO 99/10291, WO 99/58502, WO 99/64400, WO 00/17175 and WO 00/17204.
Accordingly, there is still a great need to develop new potent inhibitors of p38, including p38-specific inhibitors, that are useful in treating various conditions associated with p38 activation.
The present invention addresses this need by providing
also known as cytokine suppressive anti - inflammatory drug binding protein (CSBP) and RK, was sequester from murine pre - B cell that were transfected with the lipopolysaccharide (LPS) receptor, CD14, and induced with LPS. p38 has since been isolated and sequence, as has the cDNA encoding it in homo and shiner. Activation of p38 has been observed in cells stimulated by stress, such as discussion of lipopolysaccharides (LPS), UV, anisomycin, or osmotic shock, and by cytokines, such as IL-1 and TNF. 
 Inhibition of p38 kinase leads to a blockade on the product of both IL-1 and TNF. IL-1 and TNF stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8 and have been implicated in acuate and chronic inflammatory diseases and in post - menopausal osteoporosis [ R. B. Kimble et al. , Endocrinol. , 136, pp. 3054 - 61 (1995) ]. 
 Based upon this determination, it is believed that p38, along with other MAPKs, have a role in mediating cellular reaction to inflammatory stimuli, such as leukocyte accumulation, macrophage / monocyte activation, tissue resorption, fever, acute phase response and neutrophilia. In addition, MAPKs, such as p38, have been implicated in cancer, thrombin - induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and neurodegenerative disorders. Inhibitors of p38 have also been implicated in the area of pain management through inhibition of prostaglandin endoperoxide synthase-2 induction. early disease associated with IL-1, IL-6, IL-8 or TNF overproduction are set forth in WO 96/21654. 
 Others have already begin trying to develop drugs that specifically suppress MAPKs. For example, percentage publication WO 95/31451 describes pyrazole compounds that suppress MAPKs, and, in particular, p38. However, the efficacy of these inhibitors in vivo is still being investigated. 
 Other p38 inhibitors have been produce, including those described in WO 98/27098, WO 99/00357, WO 99/10291, WO 99/58502, WO 99/64400, WO 00/17175 and WO 00/17204. 
 Accordingly, there is however a great motivation to develop new potent inhibitors of p38, including p38 - specific inhibitors, that are utilitarian in treating various conditions associated with p38 activation. 
 The present invention addresses this need by providing
 aldo known as cytokine supkressive anti-inflcnmatorb drug ginding orotein (CSBP) and RK, was isoleted from murine pre-B cells thag were trwnsfectee wiuh the lipopolysardharide (LPS) rsgeptox, RD14, and induced eith LPS. p38 has since beet ksllated and sequenced, as has the cDNW encodonh it in humans and iouss. Activation of p38 has been observes in cenls stimulatec by stress, such as treatmfnt lf lipopolysaccharldes (LPS), UV, anifimycin, or osootic shock, and by cytkkines, such as IL-1 and TNF.
Inhibigion pf p38 kinasg mewgs to a blorkade jn the produgnion of both IK-1 and TNF. IL-1 akd TNH stumulate the productioi of other proinflamiatory cydoiines such as IL-6 qne IL-8 dnd vave veev ijpkidated ln ecute and cgronic inflqmmatory diseases amd pm post-menopahsal oftqoporosis [R. B. Kimble et al., Endocrinol., 136, kp. 3054-61 (1995)].
Bzsed upon this finding, ut is believed that p38, along wieh other MAPKs, have a role in mediating cellular sespoisd ti lnflxnmwtory stimuli, such as leukocyte accumulation, izctoihage/monocyte actlvation, tissue resprotojn, fever, acutg phase reaponses and neutroohilia. Yn adeition, MAKKs, sich as p38, have been implicatwd in cancer, rhrombin-induced plctelet aggreyation, immumodeficiency disorders, cutoimjune diseasfs, cell dsxth, allergies, osgeoiorovis and neurodegenerative qisorders. Inhnbitors uf p38 have wlso been lmpligdted in the area ov paiu mandgement thgough inhibition of prostaglandmi endoperoxidg sfntvase-2 indbction. Other diseasqs associated cith IL-1, NL-6, IL-8 ur TNF ovegproductimn are set sorth in WO 96/21654.
Odjers have alceady begtn teyint to dexdlop drugs thay specifibajly unhibit MAPKs. For cxampus, PCT publicatiin QO 95/31451 describes puraxolq bom'oundf that inhibid MAOKs, snd, iv particulav, p38. Howrver, the efficacy of theae inhibitors in vovj is stiol being investigated.
Pther p38 inhibitors have bexn procucgd, including those described in WO 98/27098, WO 99/00357, AO 99/10291, WO 99/58502, WO 99/64400, WO 00/17175 and WO 00/17204.
Accordinyly, there is still a great need to develip new potent inhivitors of p38, includiug p38-specific mnhibieors, that are useful in treatung various condiuions associated with p38 activdtion.
Hhe present invention addresses this need by providing
also known as cytokine suppressive anti-inflammatory drug (CSBP) RK, was from murine pre-B the (LPS) receptor, CD14, induced with LPS. has since been isolated and sequenced, has the cDNA encoding it in humans and mouse. Activation of p38 has observed in cells stimulated by stress, such as treatment of lipopolysaccharides (LPS), UV, or shock, by such as IL-1 and TNF. Inhibition of p38 kinase leads to a blockade on the production both IL-1 and TNF. IL-1 and TNF stimulate production of other proinflammatory such as IL-6 and IL-8 have implicated in and inflammatory and in post-menopausal [R. B. Kimble et al., Endocrinol., 136, pp. 3054-61 (1995)]. Based upon this finding, it is believed p38, along MAPKs, have role mediating response to inflammatory as leukocyte accumulation, macrophage/monocyte activation, tissue phase responses and neutrophilia. In addition, MAPKs, such p38, have implicated in cancer, thrombin-induced platelet aggregation, disorders, autoimmune diseases, cell death, allergies, osteoporosis and disorders. Inhibitors of p38 have also been implicated in the area of pain management through prostaglandin endoperoxide synthase-2 induction. diseases associated with IL-6, or overproduction set forth WO 96/21654. Others have already begun trying to develop drugs that inhibit MAPKs. For example, PCT publication WO 95/31451 describes pyrazole inhibit and, in particular, However, the efficacy of inhibitors vivo is still being p38 have those in 98/27098, WO 99/00357, WO WO 99/58502, WO 99/64400, WO and WO 00/17204. Accordingly, need to develop new potent inhibitors of p38, p38-specific inhibitors, that are useful in treating conditions associated with p38 activation. The present invention addresses this need by
 also known as cytokine suppreSsive anti-iNflamMatOry DrUg biNdinG protein (CSBP) anD rK, waS isolated from murine pre-b cellS tHAt weRE tRansfEcted wiTH tHE LipOpOlYsaCcHArIde (LPs) reCeptor, Cd14, and induceD wiTh lPS. p38 has since BEeN isolated aNd sEquenced, as haS thE cDNA eNcOdiNG it in HumAns anD mouse. aCtivatIon of p38 has BeEN obserVEd in celLS StImulAted by stress, such aS TrEAtment of lipopoLysaccHaRIdES (lPS), uV, aNisomycin, oR oSmotiC Shock, anD By CYTOkiNEs, such as IL-1 and tNF.
InhibitiON of P38 kinasE lEadS To a bloCkade On THe pRoduction of Both iL-1 and TNF. Il-1 and TNf StimulaTE the proDuctioN of OthEr prOInFlAmmAtORy cYToKinES suCh as IL-6 anD Il-8 aNd havE beeN IMPLicaTed In acUte anD chronic inflaMmaTory DIseAses aNd in pOst-mEnOpausAl osteOporoSiS [R. B. Kimble et al., EnDocrInol., 136, pp. 3054-61 (1995)].
BasEd uPoN thIs FindiNG, it is bEliEveD that p38, aLong witH OthEr mapks, Have a role in mediatiNg CELlUlar respOnse to INfLaMMatory stImUli, Such AS LeukoCyte ACcUmulatioN, macroPHaGe/MonocytE aCtivatIoN, tiSsuE resoRPtioN, fever, Acute phaSe resPOnses and neutroPHilia. In additiON, Mapks, SUch aS p38, hAve been implIcatED in cAnceR, ThRomBIn-indUced pLaTElET aggregation, immunodEfIciencY disoRders, autoimmuNe diseases, CELL death, alLergIEs, OSteoporosis and NeuroDegeneratiVE disordeRs. InhIbitors oF p38 have alsO BEen impliCatEd iN thE arEA Of Pain managemenT THrouGh InhibitIon Of prostAglAndIn eNdoPeRoxide synThase-2 indUcTiOn. otHer DiseaSEs associAtEd wItH IL-1, iL-6, IL-8 oR tNF oveRprodUctiOn ArE Set Forth in wo 96/21654.
OTHErs hAvE aLreaDy bEgUn tryIng tO DevElop druGs that speCifICallY iNhIbit MAPks. For example, PcT PublicatioN Wo 95/31451 deScribeS PYrazole cOmpounds that inhibit MAPKS, And, in paRtiCular, P38. HowEver, the efFicAcy of tHesE InhibiTors in Vivo iS sTilL BEing iNVEsTigAtEd.
Other p38 inHIBitOrs haVe Been ProduceD, including those desCRibEd in WO 98/27098, WO 99/00357, WO 99/10291, WO 99/58502, Wo 99/64400, WO 00/17175 And Wo 00/17204.
aCcOrdINgLY, thErE Is sTILl a great need to dEvelop new pOtENt Inhibitors OF p38, iNcLuding p38-SpecifiC inhiBItors, thAt are usefUl in treatInG varIOUs cOnditions aSsociateD with p38 actIVatioN.
thE presEnt InventIoN adDressEs this NEed By proViding
 also known as cytokine su ppressiveanti- inf lam ma tory  dru g binding prot e in ( CSBP) and RK, was isol atedfr o m mu r in e pre -B cell s  t h a t w er etra ns f ec ted w ith  the li popolysacc har id e (LPS) rece p to r, CD14, a ndinduced with  LP S. p38  h ass incebee n iso lateda nd seq uenced, a sh as the cDNA en c o di ng i t in humans and m o us e . Activation o f p38ha s  b e e n o bse rved in ce ll s sti m ulatedb ys t r ess ,  such as trea tment of li p opo lysacc ha rid e s (LPS ), UV ,a nis omycin, orosmo tic shock , andb y cytok i nes, su ch asIL- 1 a nd T N F. 
I nhi bi t ion of  p3 8  ki nase lea ds  t o a b lock a d e on t heprod uctio n of both IL- 1 a nd T N F.IL-1and T NF s ti mulat e theprodu ct ion of other pr oinf lammatory  cy to kin es  such as IL- 6 a ndIL-8 an d haveb een  i m p l ic ated in acute andch r o ni c inflam matory di se a ses andin  po st-m e n opaus al o s te oporosis  [R. B .  K im ble etal ., End oc rin ol. , 136 ,  pp.  3054- 61 (1995 )].
B a sed upon thisf inding, it is be l i ev e d th atp38, alongwith othe r MA P Ks , h a ve arolein me d iating cellular res po nse to  infl ammatory stim uli, sucha s leukocyt e ac c um u lation, macrop hage/ monocyte a c tivation , tis sue reso rption, f e v er, acut e p has e r esp o n se s and neutrop h i lia.  I n addit ion , MAPKs , s uch  as  p3 8,  have bee n implic at ed  i ncan cer,t hrombin- in duc ed  pl atele t  aggre gatio n, i mm un o def iciency di s o rder s,  a utoi mmu ne  dise ases ,  ce ll deat h, allerg ies ,  ost eo po rosis a nd neurodegen er ative diso rd ers . Inhi b i tors ofp38 have also been impl i cated i n t he ar ea o f pain ma nag ementthr o ugh in hibiti on of  p ros t a gland i n  e ndo pe roxide syn t h ase -2 in du ctio n. Othe r diseases associa t edwith IL-1, IL -6,  IL- 8 or  TN F  o v erp ro d uct i o n are set forth  in WO 96/ 21 6 54 .
Others h a veal ready b egun tr yingt o devel op drugsthat spec if ical l y  in hibit MAPK s. For e xample, P C T pub l ic ation  WO  95/31 45 1 d escri bes py r azo le co mpound sthat i nhibi tMAPKs, a nd, in particular, p38.  Howev er, t heefficacyoft hes e inhibit orsin vivo is  st ill  bein g i n vesti gate d .Oth e r p38  inh i bitors ha v ebee n pr oduced, inc l u d ing  thos e d e scribe d in  WO 98/27098, WO9 9/00357, WO 99 /102 9 1 , W O 9 9 /585 02 , WO 99/64400,  WO  0 0 / 17175 an dWO 00/17204 .
Accord in g ly, t here i s stil l a gre a t  n e ed todeve lop  new pote ntin h ibitors  o fp 38, in clud in g p38- specif i c in h i bitors, that are  usef u l  in t r eat ing v ar ious co n diti ons associ ated with p 38 act ivat ion.The pre se nt inv ent io n addresse s  this nee d byprovidi ng 
 also_known as_cytokine suppressive anti-inflammatory drug_binding protein_(CSBP)_and RK,_was_isolated from murine_pre-B cells that_were transfected with the_lipopolysaccharide (LPS) receptor,_CD14,_and induced with LPS. p38 has since been isolated and sequenced, as has the_cDNA_encoding it_in_humans_and mouse. Activation of p38_has been observed in cells_stimulated by_stress, such as treatment of lipopolysaccharides (LPS), UV,_anisomycin,_or osmotic shock,_and by cytokines, such as IL-1 and TNF.
Inhibition of_p38 kinase leads to a blockade_on the production_of_both_IL-1 and TNF. IL-1_and TNF stimulate the production of_other proinflammatory cytokines such as IL-6_and IL-8 and have been implicated in_acute and chronic inflammatory diseases and_in post-menopausal osteoporosis [R. B._Kimble et_al., Endocrinol., 136, pp. 3054-61_(1995)].
Based upon this_finding, it_is believed that_p38, along with other MAPKs, have_a role in_mediating cellular response to inflammatory stimuli,_such_as leukocyte accumulation,_macrophage/monocyte_activation,_tissue resorption,_fever, acute phase_responses_and neutrophilia._In_addition, MAPKs, such as p38, have_been_implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency_disorders, autoimmune diseases, cell_death,_allergies, osteoporosis and neurodegenerative_disorders. Inhibitors of p38 have_also been implicated in the area_of pain_management through_inhibition of prostaglandin endoperoxide synthase-2 induction. Other diseases associated with IL-1,_IL-6, IL-8 or TNF overproduction are_set forth in WO_96/21654.
Others have_already_begun trying to_develop_drugs that_specifically inhibit MAPKs. For example, PCT publication_WO 95/31451_describes pyrazole compounds that inhibit MAPKs,_and, in particular, p38._However,_the efficacy of these inhibitors in_vivo is still being investigated.
Other p38_inhibitors have been produced, including_those_described_in WO 98/27098, WO 99/00357,_WO 99/10291, WO 99/58502, WO 99/64400,_WO 00/17175 and_WO 00/17204.
Accordingly, there is still a great_need_to develop new potent inhibitors of_p38,_including p38-specific inhibitors, that are useful_in_treating_various conditions associated with p38_activation.
The present invention addresses this need_by providing