Discovery and structure-activity relationship of a novel spirocarbamate series of NPY Y5 antagonists

被引：6

作者：

Leslie, Colin P. ^{[1
]}

Bentley, Jonathan ^{[1
]}

Biagetti, Matteo ^{[1
]}

Contini, Stefania ^{[1
]}

Di Fabio, Romano ^{[1
]}

Donati, Daniele ^{[1
]}

Genski, Thorsten ^{[1
]}

Guery, Sebastien ^{[1
]}

Mazzali, Angelica ^{[1
]}

Merlo, Giancarlo ^{[1
]}

Pizzi, Domenica A. ^{[1
]}

Sacco, Fabiola ^{[1
]}

Seri, Catia ^{[1
]}

Tessari, Michela ^{[1
]}

Zonzini, Laura ^{[1
]}

Caberlotto, Laura ^{[1
]}

机构：

[1] GlaxoSmithKline SpA, Med Res Ctr, Neurosci Ctr Excellence Drug Discovery, I-37135 Verona, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 20期

关键词：

NPY Y5; NEUROPEPTIDE-Y; RECEPTOR ANTAGONISTS; PEPTIDE-YY; DERIVATIVES; LIGANDS;

D O I：

10.1016/j.bmcl.2010.08.041

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5] decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3 mg/kg po. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：6103 / 6107

页数：5

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