Insulin-like growth factor-1 receptor (IGF-1R) kinase inhibitors: SAR of a series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one

被引：17

作者：

Velaparthi, Upender ^{[1
]}

Saulnier, Mark G. ^{[1
]}

Wittman, Mark D. ^{[1
]}

Liu, Peiying ^{[1
]}

Frennesson, David B. ^{[1
]}

Zimmermann, Kurt ^{[1
]}

Carboni, Joan M. ^{[4
]}

Gottardis, Marco ^{[4
]}

Li, Aixin ^{[4
]}

Greer, Ann ^{[4
]}

Clarke, Wendy ^{[2
]}

Yang, Zheng ^{[3
]}

Menard, Krista ^{[4
]}

Lee, Francis Y. ^{[4
]}

Trainor, George ^{[4
]}

Vyas, Dolatrai ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Dept Discovery Chem, Wallingford, CT 06492 USA

[2] Bristol Myers Squibb Co, Dept Metab & Pharmacokinet, Wallingford, CT 06492 USA

[3] Bristol Myers Squibb Co, Dept Metab & Pharmacokinet, Princeton, NJ 08543 USA

[4] Bristol Myers Squibb Co, Dept Oncol Drug Discovery, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 10期

关键词：

Insulin-like growth factor-1 receptor (IGF-1R); Kinases; IGF; Benzimidazole; Piperazine; CYP3A4; inhibition; Solubility; VIVO ANTITUMOR-ACTIVITY; DISCOVERY; BMS-536924;

D O I：

10.1016/j.bmcl.2010.03.057

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 3-[6-(4-substitued-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：3182 / 3185

页数：4

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