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Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity |
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| Authors: | Zapf Christoph W Bloom Jonathan D McBean Jamie L Dushin Russell G Nittoli Thomas Otteng Mercy Ingalls Charles Golas Jennifer M Liu Hao Lucas Judy Boschelli Frank Hu Yongbo Vogan Erik Levin Jeremy I |
| Institution: | a Medicinal Chemistry, 401 N Middletown Road, Pearl River, NY 10965, United States b Oncology Research, 401 N Middletown Road, Pearl River, NY 10965, United States c Structural Biology & Computational Chemistry, Pfizer, 401 N Middletown Road, Pearl River, NY 10965, United States d Structural Biology & Computational Chemistry, Pfizer, 200 Cambridge Park Drive, Cambridge, MA 02139, United States |
| Abstract: | A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor. |
| Keywords: | Hsp90 inhibitors Ortho-aminobenzamides Tumor exposure Macrocycles Buchwald-Hartwig cyclization |
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