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

  • ACS Med Chem Lett. 2012 Jul 26;3(9):705-9. doi: 10.1021/ml300074j.
Tao Wang  1 ,  Michelle L Lamb  1 ,  Michael H Block  1 ,  Audrey Molina Davies  1 ,  Yongxin Han  2 ,  Ethan Hoffmann  1 ,  Stephanos Ioannidis  1 ,  John A Josey  2 ,  Zhong-Ying Liu  1 ,  Paul D Lyne  1 ,  Terry MacIntyre  1 ,  Peter J Mohr  2 ,  Charles A Omer  1 ,  Tove Sjögren  3 ,  Kenneth Thress  1 ,  Bin Wang  2 ,  Haiyun Wang  1 ,  Dingwei Yu  1 ,  Hai-Jun Zhang  1
Affiliations
  • 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.
PMID: 24900538 DOI: 10.1021/ml300074j
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.