Discovery and evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (BMS-695735), an orally efficacious inhibitor of insulin-like growth factor-1 receptor kinase with broad spectrum in vivo antitumor activity.
We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.
Velaparthi
Upender
U
Discovery Chemistry, Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Co., Wallingford, Connecticut 06492, USA. upender.velaparthi@bms.com
Wittman
Mark
M
Liu
Peiying
P
Carboni
Joan M
JM
Lee
Francis Y
FY
Attar
Ricardo
R
Balimane
Praveen
P
Clarke
Wendy
W
Sinz
Michael W
MW
Hurlburt
Warren
W
Patel
Karishma
K
Discenza
Lorell
L
Kim
Sean
S
Gottardis
Marco
M
Greer
Ann
A
Li
Aixin
A
Saulnier
Mark
M
Yang
Zheng
Z
Zimmermann
Kurt
K
Trainor
George
G
Vyas
Dolatrai
D