Discovery of 6-({4-[2-(4-tert-Butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): An Orally Active Antagonist of the Gonadotropin Releasing Hormone Receptor (GnRH-R)

被引：12

作者：

Pelletier, Jeffrey C. ^{[1
]}

Chengalvala, Murty V. ^{[2
]}

Cottom, Joshua E. ^{[2
]}

Feingold, Irene B. ^{[3
]}

Green, Daniel M. ^{[1
]}

Hauze, Diane B. ^{[1
]}

Huselton, Christine A. ^{[3
]}

Jetter, James W. ^{[1
]}

Kopf, Gregory S. ^{[2
]}

Lundquist, Joseph T., IV ^{[1
]}

Magolda, Ronald L. ^{[1
]}

Mann, Charles W. ^{[1
]}

Mehlmann, John F. ^{[1
]}

Rogers, John F. ^{[1
]}

Shanno, Linda K. ^{[2
]}

Adams, William R. ^{[3
]}

Tio, Cesario O. ^{[3
]}

Wrobel, Jay E. ^{[1
]}

机构：

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

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

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 07期

关键词：

OPTIMIZATION; AGONISTS;

D O I：

10.1021/jm801572m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule resulted in several structures with improved properties and culminated in the discovery of 6-((4-[2-(4-tertbutylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024). The compound was shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral administration.

引用

页码：2148 / 2152

页数：5

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