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Description

A cell-permeable pyrazolo-napthalenyl urea compound that acts as a highly potent, slowly binding (IC50 = 8 and 97 nM, respectively, against human p38alpha, respectively, with or without 2 h preincubation), but high affinity (t1/2 of dissociation from human p38alpha = 23 h), p38-selective inhibitor by simultaneously targeting the ATP-binding site and an adjacent DFG-out conformation-specific allosteric cavity. It inhibits JNK2alpha2 and c-Raf-1 only at much higher concentrations (IC50 = 98 nM and 1.4 µ,M, respectively) and displays little or no activity toward 10 other kinases (IC50 >20 µ,M). Shown to inhibit LPS-induced TNF-alpha production in cultures in vitro (IC50 = 18 and 780 nM using THP-1 cells and in human whole blood, respectively) and in mice in vivo (by 84% and 63%, respectively, with oral dosage of 30 mg/kg and 10 mg/kg)., A cell-permeable pyrazolo-napthalenyl urea compound that acts as a highly potent, slowly binding (IC50 = 8 and 97 nM, respectively, against human p38alpha, respectively, with or without 2 h preincubation), but high affinity (t1/2 of dissociation from human p38alpha = 23 h), p38-selective inhibitor by simultaneously targeting the ATP-binding site and an adjacent DFG-out conformation-specific allosteric cavity. It inhibits JNK2alpha2 and c-Raf-1 only at much higher concentrations (IC50 = 98 nM and 1.4 µ,M, respectively) and displays little or no activity toward 10 other kinases (IC50 >20 µ,M). Shown to inhibit LPS-induced TNF-alpha production both in vitro (IC50 = 18 and 780 nM using THP-1 cells and in human whole blood, respectively) and in mice in vivo (by 84%, 30 mg/kg p.o.).