Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia

被引：19

作者：

Moree, Wilna J. ^{[1
]}

Li, Bin-Feng ^{[1
]}

Zamani-Kord, Said ^{[1
]}

Yu, Jinghua ^{[1
]}

Coon, Timothy ^{[1
]}

Huang, Charles ^{[1
]}

Marinkovic, Dragan ^{[1
]}

Tucci, Fabio C. ^{[1
]}

Malany, Siobhan ^{[1
]}

Bradbury, Margaret J. ^{[1
]}

Hernandez, Lisa M. ^{[1
]}

Wen, Jianyun ^{[1
]}

Wang, Hua ^{[1
]}

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

Petroski, Robert E. ^{[1
]}

Jalali, Kayvon ^{[1
]}

Yang, Chun ^{[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 / 19期

关键词：

H-1-Receptor; H-1-Antihistamine; Histamine; Insomnia; Indene; CYP2D6; Biotransformation; RECEPTOR ANTAGONISTS; HEALTHY-VOLUNTEERS; DIMETHINDENE; HYPNOTICS; ENANTIOMERS; METOPROLOL; ZOLPIDEM; EFFICACY; DOXEPIN; PEOPLE;

D O I：

10.1016/j.bmcl.2010.07.117

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Analogs of the known H-1-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5874 / 5878

页数：5

共 26 条

[1]

ARNERA V, 1990, ARZNEIMITTEL-FORSCH, V40-2, P1346

[2] EFFECTS OF H-2-RECEPTOR ANTAGONISTS ON THE CENTRAL NERVOUS-SYSTEM [J].