Identification of substituted 4-aminopiperidines and 3-aminopyrrolidines as potent MCH-R1 antagonists for the treatment of obesity |
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Authors: | Kim Nick Meyers Kenneth M Mendez-Andino Jose L Warshakoon Namal C Ji Wei Wos John A Colson Annyodile Mitchell M Chrissy Davis Jan R Pinney Beth B Reizes Ofer Hu X Eric |
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Institution: | Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, OH 45040, USA. |
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Abstract: | A substituted 4-aminopiperidine was identified as showing activity in an MCH assay from an HTS effort. Subsequent structural modification of the scaffold led to the identification of a number of active MCH antagonists. 3,5-Dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)benzamide (5c) was among those with the highest binding affinity to the MCH receptor (K(i)=27nM), when variations were made at benzoyl and naphthylmethyl substitution sites from the initial HTS hit. Further optimization via piperidine ring contraction resulted in enhanced MCH activity in a 3-aminopyrrolidine series, where (R)-3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)-pyrrolidin-3-yl)benzamide (10i) was found to be an excellent MCH antagonist (K(i)=7nM). |
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