Novel pyrazolopyrimidines as highly potent B-Raf inhibitors

被引：28

作者：

Di Grandi, Martin J. ^{[1
]}

Berger, Dan M. ^{[1
]}

Hopper, Darrin W. ^{[1
]}

Zhang, Chunchun ^{[1
]}

Dutia, Minu ^{[1
]}

Dunnick, Alejandro L. ^{[1
]}

Torres, Nancy ^{[1
]}

Levin, Jeremy I. ^{[1
]}

Diamantidis, George ^{[1
]}

Zapf, Christoph W. ^{[1
]}

Bloom, Jonathan D. ^{[1
]}

Hu, YongBo ^{[2
]}

Powell, Dennis ^{[1
]}

Wojciechowicz, Donald ^{[3
]}

Collins, Karen ^{[3
]}

Frommer, Eileen ^{[3
]}

机构：

[1] Wyeth Res, Chem Sci, Pearl River, NY 10965 USA

[2] Wyeth Res, Struct Biol & Computat Chem, Pearl River, NY 10965 USA

[3] Wyeth Res, Discovery Oncol, Pearl River, NY 10965 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 24期

关键词：

B-Raf; Pyrazolopyrimidines; B-Raf inhibitors; Indazole; Phenol isostere; INDAZOLES; PATHWAY;

D O I：

10.1016/j.bmcl.2009.10.058

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：6957 / 6961

页数：5

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