Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened

被引：141

作者：

Munchhof, Michael J. ^{[1
]}

Li, Qifang ^{[2
]}

Shavnya, Andrei ^{[2
]}

Borzillo, Gary V. ^{[2
]}

Boyden, Tracey L. ^{[2
]}

Jones, Christopher S.

LaGreca, Susan D. ^{[3
]}

Martinez-Alsina, Luis ^{[2
]}

Patel, Nandini ^{[2
]}

Pelletier, Kathleen ^{[2
]}

Reiter, Larry A. ^{[4
]}

Robbins, Michael D. ^{[5
]}

Tkalcevic, George T. ^{[2
]}

机构：

[1] Michael J Munchhof LLC, Salem, CT 06420 USA

[2] Pfizer Global Res & Dev, Groton, CT 06340 USA

[3] INC Res, Old Lyme, CT 06371 USA

[4] Reiter MedChem, Mystic, CT 06355 USA

[5] Bristol Myers Squibb Co, Princeton, NJ 08540 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 02期

关键词：

Smoothened; Hedgehog signaling pathway; PF-04449913; HEDGEHOG PATHWAY; BINDING;

D O I：

10.1021/ml2002423

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibitors of the Hedgehog signaling pathway have generated a great deal of interest in the oncology area due to the mounting evidence of their potential to provide promising therapeutic options for patients. Herein, we describe the discovery strategy to overcome the issues inherent in lead structure I that resulted in the identification of Smoothened inhibitor 14(2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (PF-04449913, 26), which has been advanced to human clinical studies.

引用

页码：106 / 111

页数：6

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