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.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Biological Availability
  • Carbamates / chemical synthesis*
  • Carbamates / pharmacokinetics
  • Carbamates / pharmacology
  • Cell Line, Tumor
  • Dogs
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • Humans
  • Macaca fascicularis
  • Mice
  • Neoplasm Transplantation
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • Triazines / chemical synthesis*
  • Triazines / pharmacokinetics
  • Triazines / pharmacology

Substances

  • Antineoplastic Agents
  • Carbamates
  • Triazines
  • (4-((1-(3-fluorophenyl)methyl)-1H-indazol-5-ylamino)-5-methylpyrrolo(2,1-f)(1,2,4)triazin-6-yl)carbamic acid 3-morpholinylmethyl ester
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2