A Multivalent Approach to the Design and Discovery of Orally Efficacious 5-HT4 Receptor Agonists

被引：20

作者：

McKinnell, R. Murray ^{[1
]}

Armstrong, Scott R. ^{[2
]}

Beattie, David T. ^{[2
]}

Choi, Seok-Ki ^{[1
]}

Fatheree, Paul R. ^{[1
]}

Gendron, Roland A. L. ^{[1
]}

Goldblum, Adam ^{[1
]}

Humphrey, Patrick P. ^{[1
]}

Long, Daniel D. ^{[1
]}

Marquess, Daniel G. ^{[1
]}

Shaw, J. P. ^{[3
]}

Smith, Jacqueline A. M. ^{[4
]}

Turner, S. Derek ^{[1
]}

Vickery, Ross G. ^{[4
]}

机构：

[1] Theravance Inc, Dept Med Chem, San Francisco, CA 94080 USA

[2] Theravance Inc, Dept Pharmacol, San Francisco, CA 94080 USA

[3] Theravance Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[4] Theravance Inc, Dept Mol & Cellular Biol, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 17期

关键词：

COLONIC TRANSIT; IN-VITRO; 5-HYDROXYTRYPTAMINE; SEROTONIN; POTENT; PRUCALOPRIDE; TEGASEROD; BINDING; BENZIMIDAZOLONE; DERIVATIVES;

D O I：

10.1021/jm900881j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

5-HT4 receptor agonists such as tegaserod have demonstrated efficacy in the treatment of constipation predominant irritable bowel syndrome (IBS-C), a highly prevalent disorder characterized by chronic constipation and impairment of intestinal propulsion, abdominal bloating, and pain. The 5-HT4 receptor binding site can accommodate functionally and sterically diverse groups attached to the amine nitrogen atom of common ligands, occupying what may be termed a "secondary" binding site. Using a multivalent approach to lead discovery, we have investigated how varying the position and nature of the secondary binding group can be used as a strategy to achieve the desired 5-HT4 agonist pharmacological profile. During this study, we discovered the ability of amine-based secondary binding groups to impart exceptional gains in the binding affinity, selectivity, and functional potency of 5-HT4 agonists. Optimization of the leads generated by this approach afforded compound 26, a selective, orally efficacious 5-HT4 agonist for the potential treatment of gastrointestinal motility-related disorders.

引用

页码：5330 / 5343

页数：14

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