Design of potent and selective 2-aminobenzimidazole-based p38α MAP kinase inhibitors with excellent in vivo efficacy

被引：48

作者：

de Dios, A

Shih, C

de Uralde, BL

Sánchez, C

Del Prado, M

Cabrejas, LMM

Pleite, S

Blanco-Urgoiti, J

Lorite, MJ

Nevill, CR

Bonjouklian, R

York, J

Vieth, M

Wang, Y

Magnus, N

Campbell, RM

Anderson, BD

McCann, DJ

Giera, DD

Lee, PA

Schultz, RM

Li, LC

Johnson, LM

Wolos, JA

机构：

[1] Eli Lilly & Co, Lilly SA, Madrid 28108, Spain

[2] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 07期

关键词：

D O I：

10.1021/jm048978k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the design and discovery of a 2-amino-benzimidazole-based series of potent and highly selective p38 alpha inhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNF alpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.

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页码：2270 / 2273

页数：4

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