Discovery of 1-Amino-5H-pyrido[4,3-b]indol-4-carboxamide Inhibitors of Janus Kinase 2 (JAK2) for the Treatment of Myeloproliferative Disorders

被引：61

作者：

Lim, Jongwon ^{[1
]}

Taoka, Brandon ^{[1
]}

Otte, Ryan D. ^{[1
]}

Spencer, Kerrie ^{[1
]}

Dinsmore, Christopher J. ^{[1
]}

Altman, Michael D. ^{[4
]}

Chan, Grace ^{[3
]}

Rosenstein, Craig ^{[3
]}

Sharma, Sujata ^{[6
]}

Su, Hua-Poo ^{[6
]}

Szewczak, Alexander A. ^{[3
]}

Xu, Lin ^{[5
]}

Yin, Hong ^{[5
]}

Zugay-Murphy, Joan ^{[6
]}

Marshall, C. Gary ^{[2
]}

Young, Jonathan R. ^{[1
]}

机构：

[1] Merck & Co Inc, Dept Chem, Boston, MA 02115 USA

[2] Merck & Co Inc, Dept Oncol, Boston, MA 02115 USA

[3] Merck & Co Inc, Dept Vitro Pharmacol, Boston, MA 02115 USA

[4] Merck & Co Inc, Dept Chem Modeling & Informat, Boston, MA 02115 USA

[5] Merck & Co Inc, Dept Drug Metab & Pharmacokinet, Boston, MA 02115 USA

[6] Merck & Co Inc, Dept Struct Chem, Boston, MA 02115 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 20期

关键词：

POLYCYTHEMIA-VERA; MUTATION; EXPRESSION; BINDING; SERIES; STATS;

D O I：

10.1021/jm200909u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The JAK-STAT pathway mediates signaling by cytokines, which control survival, proliferation, and differentiation of a variety of cells. In recent years, a single point mutation (V617F) in the tyrosine kinase JAK2 was found to be present with a high incidence in myeloproliferative disorders (MPDs). This mutation led to hyperactivation of JAK.2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. The genetic, biological, and physiological evidence suggests that JAK2 inhibitors could be effective in treating MPDs. De novo design efforts of new scaffolds identified 1-amino-5H-pyrido [4,3-b]indol-4-carboxamides as a new viable lead series. Subsequent optimization of cell potency, metabolic stability, and off-target activities of the leads led to the discovery of 7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (65). Compound 65 is a potent, orally active inhibitor of JAK2 with excellent selectivity, PK profile, and in vivo efficacy in animal models.

引用

页码：7334 / 7349

页数：16

共 40 条

[21] PALLADIUM-CATALYZED CROSS-COUPLING REACTIONS OF ORGANOBORON COMPOUNDS [J].