title: Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor.
abstract: We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.
authors.affiliation: Bristol-Myers Squibb, Research and Development, Candiac, Que., Canada J5R 1J1. rruel@ambrilia.com
authors.forename: Réjean
authors.initials: R
authors.lastname: Ruel
authors.forename: Carl
authors.initials: C
authors.lastname: Thibeault
authors.forename: Alexandre
authors.initials: A
authors.lastname: L'Heureux
authors.forename: Alain
authors.initials: A
authors.lastname: Martel
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Cai
authors.forename: Donna
authors.initials: D
authors.lastname: Wei
authors.forename: Ligang
authors.initials: L
authors.lastname: Qian
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.forename: Celia
authors.initials: C
authors.lastname: D'Arienzo
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Amrita
authors.initials: A
authors.lastname: Kamath
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Yueping
authors.initials: Y
authors.lastname: Zhang
authors.forename: George
authors.initials: G
authors.lastname: Derbin
authors.forename: Barri
authors.initials: B
authors.lastname: Wautlet
authors.forename: Steven
authors.initials: S
authors.lastname: Mortillo
authors.forename: Robert
authors.initials: R
authors.lastname: Jeyaseelan
authors.forename: Benjamin
authors.initials: B
authors.lastname: Henley
authors.forename: Ravindra
authors.initials: R
authors.lastname: Tejwani
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Bhide
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C529910:5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo(2,3-b)pyridin-5-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-amine; D020533:Angiogenesis Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D011758:Pyrroles; D014227:Triazines; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2