Identification and optimization of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V3 (V1b) receptor antagonists

被引：4

作者：

Letourneau, Jeffrey J. ^{[1
]}

Riviello, Christopher M. ^{[1
]}

Li, Hong ^{[1
]}

Cole, Andrew G. ^{[1
]}

Ho, Koc-Kan ^{[1
]}

Zanetakos, Heather A. ^{[1
]}

Desai, Hema ^{[1
]}

Zhao, Jiuqiao ^{[1
]}

Auld, Douglas S. ^{[1
]}

Napier, Susan E. ^{[2
]}

Thomson, Fiona J. ^{[2
]}

Goan, Katharine A. ^{[2
]}

Morphy, J. Richard ^{[2
]}

Ohlmeyer, Michael H. J. ^{[1
]}

Webb, Maria L. ^{[1
]}

机构：

[1] Ligand Pharmaceut Inc, Cranbury, NJ 08512 USA

[2] MSD, Newhouse ML1 5SH, Lanark, Scotland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 18期

关键词：

Vasopressin (V1b) receptor; Antagonist; HPA axis; Quinazolinone; CORTICOTROPIN-RELEASING HORMONE; STRESS-RELATED DISORDERS; DIETHYL AZODICARBOXYLATE; MAJOR DEPRESSION; LEAD GENERATION; DRUG DISCOVERY; MOLECULAR TAGS; ANTIDEPRESSANTS; SSR149415; LIBRARIES;

D O I：

10.1016/j.bmcl.2010.07.118

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery, synthesis, and preliminary structure-activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS (TM) technology, had good activity in a V3 binding assay (IC(50) = 0.20 mu M), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC(50) = 0.31 mu M) and 24 (IC(50) = 0.12 mu M) with improved drug-like characteristics. (c) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5394 / 5397

页数：4

共 26 条

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