title: 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.
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.
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, USA. ashvinikumar.gavai@bms.com
authors.forename: Ashvinikumar V
authors.initials: AV
authors.lastname: Gavai
authors.forename: Brian E
authors.initials: BE
authors.lastname: Fink
authors.forename: David J
authors.initials: DJ
authors.lastname: Fairfax
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Martin
authors.forename: Lana M
authors.initials: LM
authors.lastname: Rossiter
authors.forename: Christian L
authors.initials: CL
authors.lastname: Holst
authors.forename: Soong-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Leavitt
authors.forename: Harold
authors.initials: H
authors.lastname: Mastalerz
authors.forename: Wen-Ching
authors.initials: WC
authors.lastname: Han
authors.forename: Derek
authors.initials: D
authors.lastname: Norris
authors.forename: Bindu
authors.initials: B
authors.lastname: Goyal
authors.forename: Shankar
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Bharat
authors.initials: B
authors.lastname: Patel
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.forename: Dolatrai M
authors.initials: DM
authors.lastname: Vyas
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: Chiang
authors.initials: C
authors.lastname: Yu
authors.forename: Simone
authors.initials: S
authors.lastname: Oppenheimer
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002219:Carbamates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D014227:Triazines; C545531:(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; C512478:EGFR protein, human; C508053:ERBB2 protein, human