3,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase (nNOS) inhibitors

被引：15

作者：

Annedi, Subhash C. ^{[1
]}

Maddaford, Shawn P. ^{[1
]}

Ramnauth, Jailall ^{[1
]}

Renton, Paul ^{[1
]}

Speed, Joanne ^{[1
]}

Rakhit, Suman ^{[1
]}

Andrews, John S. ^{[1
]}

Porreca, Frank ^{[2
]}

机构：

[1] NeurAxon Inc, Mississauga, ON L5K 1B3, Canada

[2] Univ Arizona, Dept Pharmacol, Tucson, AZ 85724 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 05期

关键词：

3,5-Disubstituted indole derivatives; Nitric oxide; Selective neuronal nitric oxide synthase inhibitors; Migraine; Neuropathic pain;

D O I：

10.1016/j.bmcl.2012.01.031

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

A series of 3,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). Various guanidine isosteric groups were explored at the 5-position of the indole ring, while keeping the basic amine side chain such as N-methylpiperidine ring, fixed at the 3-position of the indole ring. Compounds having 2-thiophene amidine and 2-furanyl amidine groups (7, 8, 10 and 12) showed increased activity for human neuronal NOS and good selectivity over endothelial and inducible NOS isoforms. Compound 8 was shown to reverse (10 mg/kg, ip) thermal hyperalgesia in the L5/L6 spinal nerve ligation (neuropathic pain) model and was devoid of any significant drug-drug interaction potential due to cytochrome P450 inhibition or cardiovascular liabilities associated with the inhibition of endothelial NOS. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：1980 / 1984

页数：5

共 22 条

[1]

Discovery of N-(3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-6-yl) thiophene-2-carboximidamide as a Selective Inhibitor of Human Neuronal Nitric Oxide Synthase (nNOS) for the Treatment of Pain [J].