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2-(1H-Imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chain variants of the IGF-1R inhibitor BMS-536924 |
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| Authors: | Saulnier Mark G Frennesson David B Wittman Mark D Zimmermann Kurt Velaparthi Upender Langley David R Struzynski Charles Sang Xiaopeng Carboni Joan Li Aixin Greer Ann Yang Zheng Balimane Praveen Gottardis Marco Attar Ricardo Vyas Dolatrai |
| Institution: | Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Mark.Saulnier@bms.com |
| Abstract: | A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f. |
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