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.
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.
Gavai
Ashvinikumar V
AV
Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, USA. ashvinikumar.gavai@bms.com
Fink
Brian E
BE
Fairfax
David J
DJ
Martin
Gregory S
GS
Rossiter
Lana M
LM
Holst
Christian L
CL
Kim
Soong-Hoon
SH
Leavitt
Kenneth J
KJ
Mastalerz
Harold
H
Han
Wen-Ching
WC
Norris
Derek
D
Goyal
Bindu
B
Swaminathan
Shankar
S
Patel
Bharat
B
Mathur
Arvind
A
Vyas
Dolatrai M
DM
Tokarski
John S
JS
Yu
Chiang
C
Oppenheimer
Simone
S
Zhang
Hongjian
H
Marathe
Punit
P
Fargnoli
Joseph
J
Lee
Francis Y
FY
Wong
Tai W
TW
Vite
Gregory D
GD
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
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