Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases:: Particular potency of 1H-indazole-7-carbonitrile

被引:25
作者
Cottyn, Betty [1 ]
Acher, Francine [2 ]
Ramassamy, Booma [2 ]
Alvey, Luke [1 ]
Lepoivre, Michel [3 ]
Frapart, Yves [2 ]
Stuehr, Dennis [4 ]
Mansuy, Daniel [2 ]
Boucher, Jean-Luc [2 ]
Vichard, Dominique [1 ]
机构
[1] Univ Versailles, Inst Lavoisier, CNRS, UMR 8180, F-78035 Versailles, France
[2] Univ Paris 05, CNRS, UMR 8601, Chim & Biochim Pharmacol & Toxicol Lab, F-75270 Paris, France
[3] Univ Paris 11, CNRS, UMR 8619, IBBMC, F-91105 Orsay, France
[4] Cleveland Clin, Dept Immunol, Lerner Res Fdn, Cleveland, OH 44195 USA
关键词
7-nitroindazole; substituted indazoles; nitric oxide synthase; inhibitors;
D O I
10.1016/j.bmc.2008.04.056
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A series of new 7-monosubstituted and 3,7-disubstituted indazoles have been prepared and evaluated as inhibitors of nitric oxide synthases (NOS). 1H-Indazole-7-carbonitrile (6) was found equipotent to 7-nitro-1H-indazole (1) and demonstrated preference for constitutive NOS over inducible NOS. By contrast, 1H-indazole-7-carboxamide (8) was slightly less potent but demonstrated a surprising selectivity for the neuronal NOS. Further substitution of 6 by a Br-atom at carbon-3 of the heterocycle enhanced 10-fold the inhibitory effects. Inhibition of NO formation by 6 appeared to be competitive versus both substrate and the cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin (H4B). In close analogies with 1, compound 6 strongly inhibited the NADPH oxidase activity of nNOS and induced a spin state transition of the heme-Fe-III. Our results are explained with the help of the X-ray structures that identified key-features for binding of 1 at the active site of NOS. (C) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码:5962 / 5973
页数:12
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