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-6957
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- 作者：Upender Velaparthi ; Mark Wittman ; Peiying Liu ; Joan M. Carboni ; Francis Y. Lee ; Ricardo Attar ; Praveen Balimane ; Wendy Clarke ; Michael W. Sinz ; Warren Hurlburt ; Karishma Patel ; Lorell Discenza ; Sean K
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：October 9, 2008
- 年：2008
- 卷：51
- 期：19
- 页码：5897-5900
- 全文大小：117K
- 年卷期：v.51,no.19(October 9, 2008)
- ISSN：1520-4804
文摘
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.