Influence of pKa on the biotransformation of indene H1-antihistamines by CYP2D6

被引：11

作者：

Huang, Charles ^{[1
]}

Moree, Wilna J. ^{[1
]}

Zamani-Kord, Said ^{[1
]}

Li, Bin-Feng ^{[1
]}

Tucci, Fabio C. ^{[1
]}

Malany, Siobhan ^{[1
]}

Wen, Jianyun ^{[1
]}

Wang, Hua ^{[1
]}

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

Yang, Chun ^{[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 | 2011年 / 21卷 / 03期

关键词：

H-1; receptor; H-1-antihistamine; Histamine; Insomnia; Indene; CYP2D6; Biotransformation; pK(a); CLINICAL-EVALUATION; INSOMNIA; IDENTIFICATION; DIMETHINDENE; METABOLISM; METOPROLOL; ZOLPIDEM; EFFICACY; SAFETY;

D O I：

10.1016/j.bmcl.2010.12.053

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H-1-antihistamines. Reductions in pK(a) via incorporation of a beta-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：947 / 951

页数：5

共 19 条

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