Discovery and Optimization of C-2 Methyl Imidazopyrrolopyridines as Potent and Orally Bioavailable JAK1 Inhibitors with Selectivity over JAK2

被引：55

作者：

Zak, Mark ^{[1
]}

Mendonca, Rohan ^{[1
]}

Balazs, Mercedesz ^{[8
]}

Barrett, Kathy ^{[2
]}

Bergeron, Philippe ^{[1
]}

Blair, Wade S. ^{[2
]}

Chang, Christine ^{[2
]}

Deshmukh, Gauri ^{[3
]}

DeVoss, Jason ^{[8
]}

Dragovich, Peter S. ^{[1
]}

Eigenbrot, Charles ^{[7
]}

Ghilardi, Nico ^{[4
]}

Gibbons, Paul ^{[1
]}

Gradl, Stefan ^{[1
]}

Hamman, Chris ^{[1
]}

Hanan, Emily J. ^{[1
]}

Harstad, Eric ^{[5
]}

Hewitt, Peter R. ^{[9
]}

Hurley, Christopher A. ^{[9
]}

Jin, Tian ^{[10
]}

Johnson, Adam ^{[2
]}

Johnson, Tony ^{[9
]}

Kenny, Jane R. ^{[3
]}

Koehler, Michael F. T. ^{[1
]}

Kohli, Pawan Bir ^{[2
]}

Kulagowski, Janusz J. ^{[9
]}

Labadie, Sharada ^{[1
]}

Liao, Jiangpeng ^{[10
]}

Liimatta, Marya ^{[2
]}

Lin, Zhonghua ^{[8
]}

Lupardus, Patrick J. ^{[7
]}

Maxey, Robert J. ^{[9
]}

Murray, Jeremy M. ^{[7
]}

Pulk, Rebecca ^{[1
]}

Rodriguez, Madeleine ^{[8
]}

Savage, Scott ^{[6
]}

Shia, Steven ^{[7
]}

Steffek, Micah ^{[7
]}

Ubhayakar, Savita ^{[3
]}

Ultsch, Mark ^{[7
]}

van Abbema, Anne ^{[2
]}

Ward, Stuart I. ^{[9
]}

Xiao, Ling ^{[10
]}

Xiao, Yisong ^{[10
]}

机构：

[1] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Safety Assessment, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Small Mol Proc Chem, San Francisco, CA 94080 USA

[7] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA

[8] Genentech Inc, Dept Translat Immunol, San Francisco, CA 94080 USA

[9] Argenta, Spire Green Ctr 8 9, Harlow CM19 5TR, Essex, England

[10] WuXi AppTec Co Ltd, Shanghai 200131, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 13期

关键词：

JANUS KINASE; RHEUMATOID-ARTHRITIS; SIGNAL-TRANSDUCTION; RECEPTOR; ERYTHROPOIETIN; ACTIVATION; CP-690,550; STATS; INCB018424; PREDICTION;

D O I：

10.1021/jm300628c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.

引用

页码：6176 / 6193

页数：18

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