Muth, Felix, Günther, Marcel, Bauer, Silke M., Koch, Pierre, Drueckes, Peter, Koeppler, Juergen, Trappe, Joerg and Laufer, Stefan A. (2015) Tetra-substituted pyridinylimidazoles as dual inhibitors of p38α mitogen-activated protein kinase and c-Jun N-terminal kinase 3 for potential treatment of Huntington’s Disease. Tetra-substituted pyridinylimidazoles as dual inhibitors of p38α mitogen-activated protein kinase and c-Jun N-terminal kinase 3 for potential treatment of Huntington’s Disease, 58 (1). pp. 443-456. ISSN 0022-26231520-4804

Abstract

Tetra-substituted imidazoles were designed as dual inhibitors of c-Jun N-terminal kinases 3 and p38α (mitogen-activated protein) MAP kinase. A library of 39 derivatives was prepared and evaluated in a kinase activity test for their ability to inhibit both kinases, JNK3 and p38α MAP kinase. Dual inhibitors with IC50 values down to the low double-digit nanomolar range at both enzymes were identified. The best balanced dual JNK3/p38α inhibitors being 6g (IC50 JNK3: 18 nM, p38α: 30 nM) and 14d (IC50 JNK3: 26 nM, p38α: 34 nM). They may serve as useful tool compounds for preclinical proof-of-principle studies in order to validate the synergistic role of both kinases in the progression of Huntington’s disease.

Item Type:	Article
Keywords:	kinase assays,
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/24139