Novel pyrazolopyrimidines as highly potent B-Raf inhibitors |
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Authors: | Martin J Di Grandi Dan M Berger Darrin W Hopper Chunchun Zhang Minu Dutia Alejandro L Dunnick Nancy Torres Jeremy I Levin George Diamantidis Christoph W Zapf Jonathan D Bloom YongBo Hu Dennis Powell Donald Wojciechowicz Karen Collins Eileen Frommer |
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Institution: | 1. Chemical Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA;2. Structural Biology and Computational Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA;3. Discovery Oncology, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA |
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Abstract: | A novel series of pyrazolo1,5-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. |
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