Discovery of disubstituted imidazo [4, 5-b] pyridines and purines as potent TrkA inhibitors

…, PD Lyne, T MacIntyre, PJ Mohr, CA Omer…

Index: Wang, Tao; Lamb, Michelle L.; Block, Michael H.; Davies, Audrey Molina; Han, Yongxin; Hoffmann, Ethan; Ioannidis, Stephanos; Josey, John A.; Liu, Zhong-Ying; Lyne, Paul D.; MacIntyre, Terry; Mohr, Peter J.; Omer, Charles A.; Sjoegren, Tove; Thress, Kenneth; Wang, Bin; Wang, Haiyun; Yu, Dingwei; Zhang, Hai-Jun ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 9 p. 705 - 709

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Citation Number: 8

Abstract

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 ...