Novel benzothiophene H1-antihistamines for the treatment of insomnia

被引：15

作者：

Moree, Wilna J. ^{[1
]}

Jovic, Florence ^{[1
]}

Coon, Timothy ^{[1
]}

Yu, Jinghua ^{[1
]}

Li, Bin-Feng ^{[1
]}

Tucci, Fabio C. ^{[1
]}

Marinkovic, Dragan ^{[1
]}

Gross, Raymond S. ^{[1
]}

Malany, Siobhan ^{[1
]}

Bradbury, Margaret J. ^{[1
]}

Hernandez, Lisa M. ^{[1
]}

O'Brien, Zhihong ^{[1
]}

Wen, Jianyun ^{[1
]}

Wang, Hua ^{[1
]}

Hoare, Samuel R. J. ^{[1
]}

Petroski, Robert E. ^{[1
]}

Sacaan, Aida ^{[1
]}

Madan, Ajay ^{[1
]}

Crowe, Paul D. ^{[1
]}

Beaton, Graham ^{[1
]}

机构：

[1] Neurocrine Biosci, San Diego, CA 92130 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 07期

关键词：

H1; receptor; H1-antihistamines; Insomnia; Benzothiophenes; Histamine; CHLORPHENIRAMINE; SEDATION;

D O I：

10.1016/j.bmcl.2010.01.134

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SAR of lead benzothiophene H-1-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H-1-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2316 / 2320

页数：5

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