Discovery and evaluation of spirocyclic derivatives as antagonists of the neuropeptide Y5 receptor

被引：6
|
作者：
Fichtner, Michael [1 ]
Lee, Eunsun [2 ]
Tomlinson, Elizabeth [2 ]
Scott, Dennis [3 ]
Cornelius, Peter [2 ]
Patterson, Terrell A. [2 ]
Carpino, Philip A. [1 ]
机构：
[1] Pfizer PharmaTherapeut, Dept Worldwide Med Chem, Groton, CT 06340 USA
[2] Pfizer Global Res & Dev, Dept Cardiovas Metab & Endocrine Dis, Groton, CT 06340 USA
[3] Pfizer PharmaTherapeut, Dept Pharmacokinet Dynam & Metab, Groton, CT 06340 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 08期
关键词：
Neuropeptide Y; Obesity; NPY Y5R; Drug discovery; MK-0557; Velneperit; INDUCED OBESE MICE; WEIGHT-LOSS; NPY;
D O I：
10.1016/j.bmcl.2012.02.098
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists for the treatment of obesity. Cis and trans analogs 7a and 8a were equipotent in a Y5R binding assay (K-i's <= 1 nM) and displayed good stability in human and rat liver microsome preparations. Compound 7a failed to demonstrate weight loss activity in a diet-induced obese (DIO) rat model at unbound drug levels in the brain that exceeded the Y5R K-i value by 25-fold over a 24-h time-period. (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码：2738 / 2743
页数：6
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