Small molecule antagonists of the gonadotropin-releasing hormone (GnRH) receptor: Structure-activity relationships of small heterocyclic groups appended to the 2-phenyl-4-piperazinyl-benzimidazole template

被引：10

作者：

Hauze, Diane B. ^{[1
]}

Chengalvala, Murty V. ^{[2
]}

Cottom, Joshua E. ^{[2
]}

Feingold, Irene B. ^{[3
]}

Garrick, Lloyd ^{[1
]}

Green, Daniel M. ^{[1
]}

Huselton, Christine ^{[3
]}

Kao, Wenling ^{[1
]}

Kees, Kenneth ^{[1
]}

Lundquist, Joseph T. ^{[1
]}

Mann, Charles W. ^{[1
]}

Mehlmann, John F. ^{[1
]}

Rogers, John F. ^{[1
]}

Shanno, Linda ^{[2
]}

Wrobel, Jay ^{[1
]}

Pelletier, Jeffrey C. ^{[1
]}

机构：

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

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

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 07期

关键词：

Gonadotropin releasing hormone (GnRH) receptor; 2-Phenyl-4-piperazinyl-benzimidazole; INHIBITORS; ASSAYS;

D O I：

10.1016/j.bmcl.2009.02.043

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A previous report described the serum LH suppression pharmacology of the 2-phenyl-4-piperazinyl-benzimidazole N-ethyluracil GnRH receptor antagonist 1 following oral administration in rats. A series of small heterocycles were appended to the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole template in place of the N-ethyluracil. Two imidazole analogues, 32 and 41, were shown to possess substantial in vitro potency at the target receptor (hGnRH IC(50) = 7 and 18 nM, respectively) and aqueous solubility (55 and 100 mu g/mL at pH 7.4, respectively). Both compounds had high oral bioavailability in rats and 32 was further examined in an orchidectomized rat model for serum LH suppression based on increased volume of distribution over 41. Serum LH levels trended lower in orchidectomized rats following oral administration of 32. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：1986 / 1990

页数：5

共 34 条

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