Novel N9-arenethenyl purines as potent dual Src/Abl tyrosine kinase inhibitors

  • Bioorg Med Chem Lett. 2008 Sep 1;18(17):4907-12. doi: 10.1016/j.bmcl.2008.06.042.
Yihan Wang  1 ,  William C Shakespeare ,  Wei-Sheng Huang ,  Raji Sundaramoorthi ,  Scott Lentini ,  Sasmita Das ,  Shuangying Liu ,  Geeta Banda ,  David Wen ,  Xiaotian Zhu ,  Qihong Xu ,  Jeffrey Keats ,  Frank Wang ,  Scott Wardwell ,  Yaoyu Ning ,  Joseph T Snodgrass ,  Mark I Broudy ,  Karin Russian ,  David Dalgarno ,  Tim Clackson ,  Tomi K Sawyer
Affiliations
  • 1. ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA.
PMID: 18691885 DOI: 10.1016/j.bmcl.2008.06.042
Abstract

Novel N(9)-arenethenyl purines, optimized potent dual Src/Abl tyrosine kinase inhibitors, are described. The key structural feature is a trans vinyl linkage at N(9) on the purine core which projects hydrophobic substituents into the selectivity pocket at the rear of the ATP site. Their synthesis was achieved through a Horner-Wadsworth-Emmons reaction of N(9)-phosphorylmethylpurines and substituted benzaldehydes or Heck reactions between 9-vinyl purines and aryl halides. Most compounds are potent inhibitors of both Src and Abl kinase, and several possess good oral bioavailability.