Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors

详细信息    查看全文

• 作者：Tao Wang ; Michelle L. Lamb ; Michael H. Block ; Audrey Molina Davies ; Yongxin Han ; Ethan Hoffmann ; Stephanos Ioannidis ; John A. Josey ; Zhong-Ying Liu ; Paul D. Lyne ; Terry MacIntyre ; Peter J. Mohr ; Charles A. Omer ; Tove Sj枚gren ; Kenneth Thress ; Bin Wang ; Haiyun Wang ; Dingwei Yu ; Hai-Jun Zhang
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：3
• 期：9
• 页码：705-709
• 全文大小：324K
• 年卷期：v.3,no.9(September 13, 2012)
• ISSN：1948-5875

文摘

Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.

Keywords:

Trk; kinase inhibitors; imidazo[4,5-b]pyridines; purines; cancer