Discovery of a potent p38 alpha/MAPK14 kinase inhibitor: Synthesis, in vitro/in vivo biological evaluation, and docking studies

摘要

This article reports the synthesis of new triarylpyrazole derivatives possessing urea or amide linker, and their biological activities at molecular, cellular, and in vivo levels. Compound 2b was the most potent inhibitor of p38 alpha/MAPK14 kinase (IC50 = 22 nM) among this series. Molecular docking studies were conducted to understand the kinase inhibitory variations and the basis of selectivity. Compound 2b was able to inhibit p38 alpha/MAPK14 kinase inside HEK293 cells in nanoBRET cellular kinase assay with EC50 value of 0.55 mu M, comparable to the potency of dasatinib. Compound 2b inhibited TNF-alpha production in lipopolysaccharide-induced THP-1 cells with IC50 value of 58 nM. In addition, compound 2b showed low potency against hERG. It is 62238 times less potent than E-4031 against hERG, so the risk of cardiotoxicity of the compound is very minimal. Compound 2b showed also high plasma stability in vitro in human and rat plasmas. The in vivo PK profile of compound 2b is acceptable, and its anti-inflammatory effect was comparable to diclofenac with no ulcerogenic side effect on stomach. (C) 2019 Elsevier Masson SAS. All rights reserved.