- Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases: Particular potency of 1H-indazole-7-carbonitrile
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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-FeIII. 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.
- Cottyn, Betty,Acher, Francine,Ramassamy, Booma,Alvey, Luke,Lepoivre, Michel,Frapart, Yves,Stuehr, Dennis,Mansuy, Daniel,Boucher, Jean-Luc,Vichard, Dominique
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p. 5962 - 5973
(2008/12/23)
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- Inhibition of neuronal nitric oxide synthase by 7-methoxyindazole and related substituted indazoles
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The synthesis and pharmacological evaluation of methoxyindazoles as new inhibitors of neuronal nitric oxide synthase are presented. The 7-methoxyindazole, although less potent than 7-NI, is the most active compound of the series in an in vitro enzymatic assay of neuronal nitric oxide synthase activity. This result shows that the nitro-substitution is not indispensable to the biological activity of the indazole ring. 7-Methoxyindazole possesses in vivo NOS inhibitory as well and related antinociceptive properties.
- Schumann, Pascale,Collot, Valerie,Hommet, Yannick,Gsell, Willy,Dauphin, Francois,Sopkova, Jana,MacKenzie, Eric T.,Duval, Dominique,Boulouard, Michel,Rault, Sylvain
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p. 1153 - 1156
(2007/10/03)
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