Overview | Acell-permeablepyrazolo-napthalenylureacompoundthatactsasahighlypotent,slowlybinding(IC50=8and97nM,respectively,againsthumanp38α,respectively,withorwithout2hpreincubation),buthighaffinity(t1/2ofdissociationfromhumanp38α=23h),p38-selectiveinhibitorbysimultaneouslytargetingtheATP-bindingsiteandanadjacentDFG-outconformation-specificallostericcavity.ItinhibitsJNK2α2andc-Raf-1onlyatmuchhigherconcentrations(IC50=98nMand1.4μM,respectively)anddisplayslittleornoactivitytoward10otherkinases(IC50>20μM).ShowntoinhibitLPS-inducedTNF-αproductionbothinvitro(IC50=18and780nMusingTHP-1cellsandinhumanwholeblood,respectively)andinmiceinvivo(by84%;30mg/kgp.o.). |