Design and synthesis of disubstituted thiophene and thiazole based inhibitors of JNK

  • Bioorg Med Chem Lett. 2010 Dec 15;20(24):7303-7. doi: 10.1016/j.bmcl.2010.10.066.
Roy K Hom  1 ,  Simeon Bowers ,  Jennifer M Sealy ,  Anh P Truong ,  Gary D Probst ,  Martin L Neitzel ,  R Jeffrey Neitz ,  Larry Fang ,  Louis Brogley ,  Jing Wu ,  Andrei W Konradi ,  Hing L Sham ,  Gergely Tóth ,  Hu Pan ,  Nanhua Yao ,  Dean R Artis ,  Kevin Quinn ,  John-Michael Sauer ,  Kyle Powell ,  Zhao Ren ,  Frédérique Bard ,  Ted A Yednock ,  Irene Griswold-Prenner
Affiliations
  • 1. Department of Chemical Sciences, Elan Pharmaceuticals, South San Francisco, CA 94080, USA. [email protected]
PMID: 21071223 DOI: 10.1016/j.bmcl.2010.10.066
Abstract

From high throughput screening, we discovered compound 1, the prototype for a series of disubstituted thiophene inhibitors of JNK which is selective towards closely related MAP kinases p38 and ERK2. Herein we describe the evolution of these compounds to a novel class of thiophene and thiazole JNK inhibitors that retain favorable solubility, permeability, and P-gp properties for development as CNS agents for treatment of neurodegeneration. Compound 61 demonstrated JNK3 IC(50)=77 nM and retained the excellent broad kinase selectivity observed for the series.

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