Identification of substituted 4-aminopiperidines and 3-aminopyrrolidines as potent MCH-R1 antagonists for the treatment of obesity

被引：11

作者：

Kim, Nick ^{[1
]}

Meyers, Kenneth M. ^{[1
]}

Mendez-Andino, Jose L. ^{[1
]}

Warshakoon, Namal C. ^{[1
]}

Ji, Wei ^{[1
]}

Wos, John A. ^{[1
]}

Colson, Annyodile ^{[1
]}

Mitchell, M. Chrissy ^{[1
]}

Davis, Jan R. ^{[1
]}

Pinney, Beth B. ^{[1
]}

Reizes, Ofer ^{[1
]}

Hu, X. Eric ^{[1
]}

机构：

[1] Procter & Gamble Pharmaceut, Mason, OH 45040 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 20期

关键词：

MCH-R1; antagonist; obesity; aminopiperidine; aminopyrrolidine;

D O I：

10.1016/j.bmcl.2006.07.053

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 = 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 (K-i = 7 nM). (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：5445 / 5450

页数：6

共 19 条

[1] THE MELANIN-CONCENTRATING HORMONE SYSTEM OF THE RAT-BRAIN - AN IMMUNIZATION AND HYBRIDIZATION HISTOCHEMICAL CHARACTERIZATION [J].