Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor

  • J Med Chem. 2007 Feb 22;50(4):611-26. doi: 10.1021/jm061107l.
Brian L Hodous  1 ,  Stephanie D Geuns-Meyer ,  Paul E Hughes ,  Brian K Albrecht ,  Steve Bellon ,  James Bready ,  Sean Caenepeel ,  Victor J Cee ,  Stuart C Chaffee ,  Angela Coxon ,  Maurice Emery ,  Jenne Fretland ,  Paul Gallant ,  Yan Gu ,  Doug Hoffman ,  Rebecca E Johnson ,  Richard Kendall ,  Joseph L Kim ,  Alexander M Long ,  Michael Morrison ,  Philip R Olivieri ,  Vinod F Patel ,  Anthony Polverino ,  Paul Rose ,  Paul Tempest ,  Ling Wang ,  Douglas A Whittington ,  Huilin Zhao
Affiliations
  • 1. Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139-1581, USA. [email protected]
PMID: 17253678 DOI: 10.1021/jm061107l
Abstract

Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase TIE-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of TIE-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting TIE-2 signaling, we developed a series of potent and orally bioavailable small molecule TIE-2 kinase inhibitors with selectivity over Other Kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective TIE-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of Kinases, good oral exposure, and in vivo inhibition of TIE-2 phosphorylation.

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