Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists

被引：35

作者：

Bell, Ian M. ^{[1
]}

Bednar, Rodney A. ^{[1
]}

Fay, John F. ^{[1
]}

Gallicchio, Steven N. ^{[1
]}

Hochman, Jerome H. ^{[1
]}

McMasters, Daniel R. ^{[1
]}

Miller-Stein, Cynthia ^{[1
]}

Moore, Eric L. ^{[1
]}

Mosser, Scott D. ^{[1
]}

Pudvah, Nicole T. ^{[1
]}

Quigley, Amy G. ^{[1
]}

Salvatore, Christopher A. ^{[1
]}

Stump, Craig A. ^{[1
]}

Theberge, Cory R. ^{[1
]}

Wong, Bradley K. ^{[1
]}

Zartman, C. Blair ^{[1
]}

Zhang, Xu-Fang ^{[1
]}

Kane, Stefanie A. ^{[1
]}

Graham, Samuel L. ^{[1
]}

Vacca, Joseph P. ^{[1
]}

Williams, Theresa M. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 24期

关键词：

CGRP receptor antagonists; CGRP; migraine; spirohydantoin;

D O I：

10.1016/j.bmcl.2006.09.045

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compound 12, a potent CGRP receptor antagonist (K-i = 21 nM) with good oral bioavailability in three species. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：6165 / 6169

页数：5

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