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

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 compounds 2d and 3a.

SUBMITTER: Wang T

PROVIDER: S-EPMC4025776 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Wang Tao T Lamb Michelle L ML Block Michael H MH Davies Audrey Molina AM Han Yongxin Y Hoffmann Ethan E Ioannidis Stephanos S Josey John A JA Liu Zhong-Ying ZY Lyne Paul D PD MacIntyre Terry T Mohr Peter J PJ Omer Charles A CA Sjögren Tove T Thress Kenneth K Wang Bin B Wang Haiyun H Yu Dingwei D Zhang Hai-Jun HJ

ACS medicinal chemistry letters 20120726 9

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. ...[more]

PMID: 24900538

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