Discovery and preclinical evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS-599626), a selective and orally efficacious inhibitor of human epidermal growth factor receptor 1 and 2 kinases

  • J Med Chem. 2009 Nov 12;52(21):6527-30. doi: 10.1021/jm9010065.
Ashvinikumar V Gavai  1 ,  Brian E Fink ,  David J Fairfax ,  Gregory S Martin ,  Lana M Rossiter ,  Christian L Holst ,  Soong-Hoon Kim ,  Kenneth J Leavitt ,  Harold Mastalerz ,  Wen-Ching Han ,  Derek Norris ,  Bindu Goyal ,  Shankar Swaminathan ,  Bharat Patel ,  Arvind Mathur ,  Dolatrai M Vyas ,  John S Tokarski ,  Chiang Yu ,  Simone Oppenheimer ,  Hongjian Zhang ,  Punit Marathe ,  Joseph Fargnoli ,  Francis Y Lee ,  Tai W Wong ,  Gregory D Vite
Affiliations
  • 1. Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, USA. [email protected]
PMID: 19821562 DOI: 10.1021/jm9010065
Abstract

Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.