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ACS Med Chem Lett. 2012 Jul 26;3(9):705-9. doi: 10.1021/ml300074j. eCollection 2012 Sep 13.

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

Author information

1
Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
2
Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
3
Discovery Sciences, Innovative Medicines, AstraZeneca , Pepparedsleden S431 83 Mölndal, Sweden.

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.

KEYWORDS:

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

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