1. Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases: particular potency of 1H-indazole-7-carbonitrile.
- Author
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Cottyn B, Acher F, Ramassamy B, Alvey L, Lepoivre M, Frapart Y, Stuehr D, Mansuy D, Boucher JL, and Vichard D
- Subjects
- Animals, Binding Sites, Catalysis, Cell Line, Indazoles metabolism, Mice, Nitric Oxide metabolism, Nitric Oxide Synthase metabolism, Nitric Oxide Synthase Type I chemistry, Nitric Oxide Synthase Type I metabolism, Nitric Oxide Synthase Type II chemistry, Nitric Oxide Synthase Type III chemistry, Spectrophotometry, Ultraviolet, Structure-Activity Relationship, Indazoles chemical synthesis, Indazoles pharmacology, Nitric Oxide Synthase antagonists & inhibitors
- Abstract
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 (H(4)B). 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.
- Published
- 2008
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