Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy.
Preclinical and emerging clinical evidence suggests that inhibiting insulin-like growth factor 1 receptor (IGF-1R) signaling may offer a promising therapeutic strategy for the treatment of several types of cancer. This Letter describes the medicinal chemistry effort towards a series of 8-amino-imidazo[1,5-a]pyrazine derived inhibitors of IGF-1R which features a substituted quinoline moiety at the C1 position and a cyclohexyl linking moiety at the C3 position. Lead optimization efforts which included the optimization of structure-activity relationships and drug metabolism and pharmacokinetic properties led to the identification of compound 9m, a potent, selective and orally bioavailable inhibitor of IGF-1R with in vivo efficacy in an IGF-driven mouse xenograft model.
(OSI) Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA. mjin@osip.com
Meizhong
M
Jin
Andrew
A
Kleinberg
Andy
A
Cooke
Prafulla C
PC
Gokhale
Kenneth
K
Foreman
Hanqing
H
Dong
Kam W
KW
Siu
Mark A
MA
Bittner
Kristen M
KM
Mulvihill
Yan
Y
Yao
Darla
D
Landfair
Matthew
M
O'Connor
Gilda
G
Mak
Jonathan A
JA
Pachter
Robert
R
Wild
Maryland
M
Rosenfeld-Franklin
Qunsheng
Q
Ji
Mark J
MJ
Mulvihill
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007093:Imidazoles / Q000737:chemistry*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011719:Pyrazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C029899:imidazole; D017526:Receptor, IGF Type 1