【文章名】Discovery and Evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperi din-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 Kina
Discovery and Evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperi din-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 Kina
作者
Velaparthi, Upender;Wittman, Mark;Liu, Peiying;Carboni, Joan M.;Lee, Francis Y.;Attar, Ricardo;Balimane, Praveen;Clarke, Wendy;Sinz, Michael W.;Hurlburt, Warren;Patel, Karishma;Discenza, Lorell;Kim, Sean;Gottardis, Marco;Greer, Ann;Li, Aixin;Saulnier, Mar
[摘要]：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 compd. was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aq. soly., and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735, I), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.
