Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2

被引：57

作者：

Zak, Mark ^{[1
]}

Hurley, Christopher A. ^{[10
]}

Ward, Stuart I. ^{[10
]}

Bergeron, Philippe ^{[1
]}

Barrett, Kathy ^{[2
]}

Balazs, Mercedesz ^{[9
]}

Blair, Wade S. ^{[2
]}

Bull, Richard ^{[10
]}

Chakravarty, Paroma ^{[6
]}

Chang, Christine ^{[2
]}

Crackett, Peter ^{[10
]}

Deshmukh, Gauri ^{[3
]}

DeVoss, Jason ^{[9
]}

Dragovich, Peter S. ^{[1
]}

Eigenbrot, Charles ^{[8
]}

Ellwood, Charles ^{[10
]}

Gaines, Simon ^{[10
]}

Ghilardi, Nico ^{[4
]}

Gibbons, Paul ^{[1
]}

Gradl, Stefan ^{[1
]}

Gribling, Peter ^{[9
]}

Hamman, Chris ^{[1
]}

Harstad, Eric ^{[5
]}

Hewitt, Peter ^{[10
]}

Johnson, Adam ^{[2
]}

Johnson, Tony ^{[10
]}

Kenny, Jane R. ^{[3
]}

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

Kohli, Pawan Bir ^{[2
]}

Labadie, Sharada ^{[1
]}

Lee, Wyne P. ^{[9
]}

Liao, Jiangpeng ^{[11
]}

Liimatta, Marya ^{[2
]}

Mendonca, Rohan ^{[1
]}

Narukulla, Raman ^{[10
]}

Pulk, Rebecca ^{[1
]}

Reeve, Austin ^{[10
]}

Savage, Scott ^{[7
]}

Shia, Steven ^{[8
]}

Steffek, Micah ^{[8
]}

Ubhayakar, Savita ^{[3
]}

van Abbema, Anne ^{[2
]}

Aliagas, Ignacio ^{[1
]}

Avitabile-Woo, Barbara ^{[10
]}

Xiao, Yisong ^{[11
]}

Yang, Jing ^{[11
]}

Kulagowski, Janusz J. ^{[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 Pharmaceut Sci, San Francisco, CA 94080 USA

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

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

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

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

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 11期

关键词：

LIVER MICROSOMAL STABILITY; IN-SILICO MODELS; MYELOPROLIFERATIVE DISORDERS; ENANTIOSELECTIVE SYNTHESIS; MEDICINAL CHEMISTS; JAK/STAT PATHWAY; DRUG DISCOVERY; KINASE DOMAINS; JANUS KINASES; PREDICTION;

D O I：

10.1021/jm4004895

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

引用

页码：4764 / 4785

页数：22

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