2. Academic Validation
  3. Identification of 4-aminopyrazolylpyrimidines as potent inhibitors of Trk kinases

Identification of 4-aminopyrazolylpyrimidines as potent inhibitors of Trk kinases

  • J Med Chem. 2008 Aug 14;51(15):4672-84. doi: 10.1021/jm800343j.
Tao Wang 1,  Michelle L Lamb,  David A Scott,  Haixia Wang,  Michael H Block,  Paul D Lyne,  John W Lee,  Audrey M Davies,  Hai-Jun Zhang,  Yanyi Zhu,  Fei Gu,  Yongxin Han,  Bin Wang,  Peter J Mohr,  Robert J Kaus,  John A Josey,  Ethan Hoffmann,  Ken Thress,  Terry Macintyre,  Haiyun Wang,  Charles A Omer,  Dingwei Yu
Affiliations

Affiliation

  • 1 Department of Cancer Chemistry, AstraZeneca R&D Boston, Waltham, Massachusetts 02451, USA. tao.wang@astrazeneca.com
PMID: 18646745 DOI: 10.1021/jm800343j
Abstract

The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of Cancer and Other indications in vivo.

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