Implications for selectivity of 3,4-diarylquinolinones as p38alphaMAP kinase inhibitors

Bioorganic & Medicinal Chemistry Letters
Christian PeiferStefan Laufer

Abstract

In this study we report on the specificity profiling of the MAP kinase inhibitors 1, 2, and 3 in a panel of 78 protein kinases including the MAPK isoforms p38(alpha,beta,gamma,delta), JNK1/2/3, and ERK1/2/8 showing 3-(4-fluorophenyl)-4-pyridin-4-ylquinolin-2(1H)-one (1) to be highly selective for p38alphaMAPK with an IC(50) of 1.8 microM. In contrast, besides p38alpha the isoxazoles 2 and 3 significantly inhibited JNK2/3 and further kinases beyond the MAPK family such as PKA, PKD, Lck, and CK1. By using sequence alignment and homology models of different members of the MAPK family the binding mode determining selectivity of 1 for the p38alpha isoform was investigated. For lead optimization of 1 a straightforward tandem-Buchwald-aldol synthetic approach toward the flexible decoration of the quinolin-2(1H)-one scaffold was employed. SAR for derivatives of 1 at the isolated p38alphaMAPK are presented.

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Citations

Jul 2, 2009·Journal of Chemical Biology·Lynette A Smyth, Ian Collins
Apr 1, 2011·Saudi Pharmaceutical Journal : SPJ : the Official Publication of the Saudi Pharmaceutical Society·Nilesh J Thumar, Manish P Patel
Oct 1, 2016·Chemical Reviews·Paula Ruiz-Castillo, Stephen L Buchwald
Sep 22, 2018·Organic & Biomolecular Chemistry·Ailada CharoenpolChutima Kuhakarn
May 31, 2013·Organic & Biomolecular Chemistry·Jia-Fei PoonPeter Dinér
Oct 11, 2017·Chemical Science·Xinyao LiNing Jiao
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Roberto RomeoDaniela Iannazzo
Mar 17, 2010·European Journal of Pharmacology·Lenka MunozAlaina J Ammit
May 8, 2010·The Journal of Organic Chemistry·Kiyofumi InamotoTakayuki Doi
Dec 3, 2009·Journal of the American Chemical Society·Jeffrey R SimardDaniel Rauh
Feb 17, 2015·The Journal of Organic Chemistry·Weiguo WangZhenghu Xu
Dec 10, 2016·The Journal of Organic Chemistry·Tsukasa MurayamaYoshihiko Yamamoto

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