Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine-based selective inhibitors of human neuronal nitric oxide synthase (nNOS)

被引：8
作者：
Annedi, Subhash C.
Ramnauth, Jailall
Cossette, Michele
Maddaford, Shawn P.
Dove, Peter
Rakhit, Suman
Andrews, John S.
Porreca, Frank [1 ]
机构：
[1] Univ Arizona, Dept Pharmacol, Tucson, AZ USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 07期
基金：
加拿大自然科学与工程研究理事会;
关键词：
2,3,4,5-Tetrahydro-1H-benzo[b]azepine derivatives Nitric oxide; Nitric oxide synthase; Selective neuronal nitric oxide synthase inhibitors; Neuropathic pain; INDOLE-DERIVATIVES; DISCOVERY; DESIGN;
D O I：
10.1016/j.bmcl.2012.02.004
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure-activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzo[b]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (+/-)-39, and (+/-)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K+ channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels). (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码：2510 / 2513
页数：4
相关论文
共 23 条
[1]   Nitric oxide synthases: structure, function and inhibition [J].
Alderton, WK ;
Cooper, CE ;
Knowles, RG .
BIOCHEMICAL JOURNAL, 2001, 357 (03) :593-615
[2]   Discovery of cis-N-(1-(4-(Methylamino)cyclohexyl)indolin-6-yl)thiophene-2-carboximidamide: A 1,6-Disubstituted Indoline Derivative as a Highly Selective Inhibitor of Human Neuronal Nitric Oxide Synthase (nNOS) without Any Cardiovascular Liabilities [J].
Annedi, Subhash C. ;
Ramnauth, Jailall ;
Maddaford, Shawn P. ;
Renton, Paul ;
Rakhit, Suman ;
Mladenova, Gabriela ;
Dove, Peter ;
Silverman, Sarah ;
Andrews, John S. ;
Felice, Milena D. ;
Porreca, Frank .
JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (02) :943-955
[3]   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].
Annedi, Subhash C. ;
Maddaford, Shawn P. ;
Mladenova, Gabriela ;
Ramnauth, Jailall ;
Rakhit, Suman ;
Andrews, John S. ;
Lee, David K. H. ;
Zhang, Dongqin ;
Porreca, Frank ;
Bunton, David ;
Christie, Lee .
JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (20) :7408-7416
[4]  
BERCOTVATTERONI M, 1962, ANN CHIM FRANCE, V7, P303
[5]   Selective neuronal nitric oxide synthase inhibitors [J].
Erdal, EP ;
Litzinger, EA ;
Seo, JW ;
Zhu, YQ ;
Ji, HT ;
Silverman, RB .
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (07) :603-624
[6]  
Haitao J., 2009, J MED CHEM, V52, P779
[7]   HYPERTENSION IN MICE LACKING THE GENE FOR ENDOTHELIAL NITRIC-OXIDE SYNTHASE [J].
HUANG, PL ;
HUANG, ZH ;
MASHIMO, H ;
BLOCH, KD ;
MOSKOWITZ, MA ;
BEVAN, JA ;
FISHMAN, MC .
NATURE, 1995, 377 (6546) :239-242
[8]   New ammonia equivalents for the Pd-catalyzed amination of aryl halides [J].
Huang, XH ;
Buchwald, SL .
ORGANIC LETTERS, 2001, 3 (21) :3417-3419
[9]   Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors [J].
Ji, Haitao ;
Stanton, Benjamin Z. ;
Igarashi, Jotaro ;
Li, Huiying ;
Martasek, Pavel ;
Roman, Linda J. ;
Poulos, Thomas L. ;
Silverman, Richard B. .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2008, 130 (12) :3900-3914
[10]  
KIM SH, 1992, PAIN, V50, P355, DOI 10.1016/0304-3959(92)90041-9
123