2. Academic Validation
  3. Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor

Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor

  • J Med Chem. 2006 Apr 6;49(7):2143-6. doi: 10.1021/jm051106d.
Rajeev S Bhide 1,  Zhen-Wei Cai,  Yong-Zheng Zhang,  Ligang Qian,  Donna Wei,  Stephanie Barbosa,  Louis J Lombardo,  Robert M Borzilleri,  Xiaoping Zheng,  Laurence I Wu,  Joel C Barrish,  Soong-Hoon Kim,  Kenneth Leavitt,  Arvind Mathur,  Leslie Leith,  Sam Chao,  Barri Wautlet,  Steven Mortillo,  Robert Jeyaseelan Sr,  Daniel Kukral,  John T Hunt,  Amrita Kamath,  Aberra Fura,  Viral Vyas,  Punit Marathe,  Celia D'Arienzo,  George Derbin,  Joseph Fargnoli
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. [email protected]
PMID: 16570908 DOI: 10.1021/jm051106d
Abstract

A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.

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