Discovery of novel dihydroimidazothiazole derivatives as p53-MDM2 protein-protein interaction inhibitors: Synthesis, biological evaluation and structure-activity relationships

被引：13

作者：

Miyazaki, Masaki ^{[1
]}

Kawato, Haruko ^{[1
]}

Naito, Hiroyuki ^{[1
]}

Ikeda, Masahiro ^{[1
]}

Miyazaki, Masaya ^{[2
]}

Kitagawa, Mayumi ^{[2
]}

Seki, Takahiko ^{[2
]}

Fukutake, Setsuko ^{[2
]}

Aonuma, Masashi ^{[2
]}

Soga, Tsunehiko ^{[1
]}

机构：

[1] Daiichi Sankyo Co Ltd, R&D Div, Lead Discovery & Optimizat Res Labs 2, Shinagawa Ku, Tokyo 1408710, Japan

[2] Daiichi Sankyo Co Ltd, R&D Div, Oncol Res Labs, Edogawa Ku, Tokyo 1348630, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 20期

关键词：

MDM2; p53; Dihydroimidazothiazole; Protein-protein interaction inhibitor; STRUCTURE-BASED DESIGN; MDM2; AMPLIFICATION; CANCER;

D O I：

10.1016/j.bmcl.2012.08.086

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting with Nutlins as an initial lead, we designed and generated bicyclic scaffolds aiming to place cis-bischlorophenyl moiety at the equivalent location where the hydrophobic interaction with MDM2 could be expected. As a result, we discovered novel MDM2 inhibitors possessing a dihydroimidazothiazole scaffold. Further exploration of the side chains on the dihydroimidazothiazole scaffold aided by molecular modeling resulted in compounds exhibiting almost comparable in vitro potency to Nutlin-3a. (c) 2012 Elsevier Ltd. All rights reserved.

引用

页码：6338 / 6342

页数：5

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