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

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 11; pp. 5962 - 5973
• Main Authors: Cottyn, Betty, Acher, Francine, Ramassamy, Booma, Alvey, Luke, Lepoivre, Michel, Frapart, Yves, Stuehr, Dennis, Mansuy, Daniel, Boucher, Jean-Luc, Vichard, Dominique
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 2008
• Subjects: 7-Nitroindazole; Inhibitors; Nitric oxide synthase; Substituted indazoles; DTT; ImH; NO 2-arg; H 4B; Hepes; LS; n-, i- and eNOS; SOD; HS; nNOS oxy; CaM; l-arg; NOS; Inhibitors; 7-Nitroindazole; Nitric oxide synthase; Substituted indazoles
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.04.056

A series of new 7-monosubstituted and 3,7-disubstituted indazoles have been synthesized and tested as inhibitors of nitric oxide synthases. A series of new 7-monosubstituted and 3,7-disubstituted indazoles have been prepared and evaluated as inhibitors of nitric oxide synthases (NOS). 1 H-Indazole-7-carbonitrile ( 6) was found equipotent to 7-nitro-1 H-indazole ( 1) and demonstrated preference for constitutive NOS over inducible NOS. By contrast, 1 H-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 (6 R)-5,6,7,8-tetrahydro- l-biopterin (H 4B). 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.