Proline bis-amides as potent dual orexin receptor antagonists

被引：65

作者：

Bergman, Jeffrey M. ^{[1
]}

Roecker, Anthony J. ^{[1
]}

Mercer, Swati P. ^{[1
]}

Bednar, Rodney A. ^{[1
]}

Reiss, Duane R. ^{[2
]}

Ransom, Richard W. ^{[2
]}

Harrell, C. Meacham ^{[2
]}

Pettibone, Douglas J. ^{[2
]}

Lemaire, Wei ^{[2
]}

Murphy, Kathy L. ^{[2
]}

Li, Chunze ^{[3
]}

Prueksaritanont, Thomayant ^{[3
]}

Winrow, Christopher J. ^{[2
]}

Renger, John J. ^{[2
]}

Koblan, Kenneth S. ^{[2
]}

Hartman, George D. ^{[1
]}

Coleman, Paul J. ^{[1
]}

机构：

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

[2] Merck Res Labs, Dept Depress & Circadian Disorders, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 04期

关键词：

D O I：

10.1016/j.bmcl.2008.01.001

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of OX2R/OX1R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions were discovered. N-methylation of the benzimidazole moiety within the lead structure significantly reduced P-gp susceptibility while increasing potency, giving rise to good brain penetration. A compound from this series has demonstrated in vivo central activity when dosed peripherally in a pharmacodynamic model of orexin activity. Published by Elsevier Ltd.

引用

页码：1425 / 1430

页数：6

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