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Heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 receptor antagonist |
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| Authors: | Guanglin Luo Ling Chen Shuanghua Hu Yazhong Huang Gail Mattson Lawrence G Iben John W Russell Wendy J Clarke John B Hogan Ildiko Antal-Zimanyi Graham S Poindexter |
| Institution: | 1. Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA;2. Disease Sciences and Biologics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA |
| Abstract: | A convergent synthesis route for the heterocyclic modification of a novel bicyclo3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported. Two heterocyclic analogs 9 and 10 showed comparable Y1 binding potency to 2, but with improved aqueous solubility. Compound 9 demonstrated reduced spontaneous nocturnal food intake in a rat model when dosed ip. Compound 9 was also shown to be orally bioavailable and brain penetrable. |
| Keywords: | Obesity NPY1 receptor antagonist Bicyclo[3 1 0]hexanes |
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