Article ID Journal Published Year Pages File Type
1374135 Bioorganic & Medicinal Chemistry Letters 2006 6 Pages PDF
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 (Ki = 27 nM), 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 (Ki = 7 nM).

Graphical abstractStructure modification of 4-aminopiperidine, an HTS hit, led to the identification of 4-piperidinylbenzamide (5c) as a potent MCH antagonist (Ki = 27 nM). Further optimization via piperidine ring contraction resulted in enhanced activity in a 3-aminopyrrolidine series, where 3-pyrrolidinylbenzamide (10i) was found to be an excellent MCH antagonist (Ki = 7 nM).Figure optionsDownload full-size imageDownload as PowerPoint slide

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