2-phenyl-4-piperazinylbenzimidazoles: Orally active inhibitors of the gonadotropin releasing hormone (GnRH) receptor

被引：25

作者：

Pelletier, Jeffrey C. ^{[1
]}

Chengalvala, Murty ^{[2
]}

Cottom, Josh ^{[2
]}

Feingold, Irene ^{[3
]}

Garrick, Lloyd ^{[1
]}

Green, Daniel ^{[1
]}

Hauze, Diane ^{[1
]}

Huselton, Christine ^{[3
]}

Jetter, James ^{[1
]}

Kao, Wenling ^{[1
]}

Kopf, Gregory S. ^{[2
]}

Lundquist, Joseph T. ^{[1
]}

Mann, Charles ^{[1
]}

Mehlmann, John ^{[1
]}

Rogers, John ^{[1
]}

Shanno, Linda ^{[2
]}

Wrobel, Jay ^{[1
]}

机构：

[1] Wyeth Res, Dept Chem & Screening Sci, Collegeville, PA 19426 USA

[2] Wyeth Res, Dept Womens Hlth & Musculoskeletal Biol, Collegeville, PA 19426 USA

[3] Wyeth Res, Dept Drug Safety & Metab, Collegeville, PA 19426 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 13期

关键词：

gonadotropin releasing hormone antagonist; oral activity; small molecule; pharmaceutical profiling;

D O I：

10.1016/j.bmc.2008.05.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Antagonism of the gonadotropin releasing hormone (GnRH) receptor has shown positive clinical results in numerous reproductive tissue disorders such as endometriosis, prostate cancer and others. Traditional therapy has been limited to peptide agonists and antagonists. Recently, small molecule GnRH antagonists have emerged as potentially new treatments. This article describes the discovery of 2-phenyl-4-piperazinylbenzimidazoles as small molecule GnRH antagonists with nanomolar potency in in vitro binding and functional assays, excellent bioavailability (rat % F > 70) and demonstrated oral activity in a rat model having shown significant serum leuteinizing hormone (LH) suppression. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6617 / 6640

页数：24

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