PH-797804 is an ATP-competitive, readily reversible inhibitor of the alpha isoform of human p38 MAP kinase, exhibiting a K(i) = 5.8 nM. PH-797804 blocks inflammation-induced production of cytokines and proinflammatory mediators in human monocyte and synovial fibroblast cell systems, such as prostaglandin E(2), at concentrations that parallel inhibition of cell-associated p38 MAP kinase. PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys after oral dosing. PH-797804 exhibited exceptionally high specificity against MAP kinases and the related kinases. No cross-reactivity was observed in large panels of kinase screens (selectivity ratio of >500-fold). In cellular assays, PH-797804 demonstrated superior potency and selectivity consistent with the biochemical measurements. Finally, PH-797804 reduced tumor necrosis factor-alpha and interleukin-6 production in clinical studies after endotoxin administration in a dose-dependent manner, paralleling inhibition of the target enzyme.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 90 mg/mL|
Discovery and characterization of atropisomer PH-797804, a p38 MAP kinase inhibitor, as a clinical drug candidate.
Xing L, et al. ChemMedChem. 2012 Feb 6;7(2):273-80. PMID: 22174080.
Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation.
Hope HR, et al. J Pharmacol Exp Ther. 2009 Dec;331(3):882-95. PMID: 19720877.
Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804.
Xing L, et al. Biochemistry. 2009 Jul 14;48(27):6402-11. PMID: 19496616.
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