Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase

被引：93

作者：

Trejo, A ^{[1
]}

Arzeno, H ^{[1
]}

Browner, M ^{[1
]}

Chanda, S ^{[1
]}

Cheng, S ^{[1
]}

Comer, DD ^{[1
]}

Dalrymple, SA ^{[1
]}

Dunten, P ^{[1
]}

Lafargue, J ^{[1
]}

Lovejoy, B ^{[1
]}

Freire-Moar, J ^{[1
]}

Lim, J ^{[1
]}

Mcintosh, J ^{[1
]}

Miller, J ^{[1
]}

Papp, E ^{[1
]}

Reuter, D ^{[1
]}

Roberts, R ^{[1
]}

Sanpablo, F ^{[1
]}

Saunders, J ^{[1
]}

Song, K ^{[1
]}

Villasenor, A ^{[1
]}

Warren, SD ^{[1
]}

Welch, M ^{[1
]}

Weller, P ^{[1
]}

Whiteley, PE ^{[1
]}

Zeng, L ^{[1
]}

Goldstein, DM ^{[1
]}

机构：

[1] Roche Palo Alto LLC, Dept Med Chem, Palo Alto, CA 94304 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2003年 / 46卷 / 22期

关键词：

D O I：

10.1021/jm0301787

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.

引用

页码：4702 / 4713

页数：12

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