Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases: particular potency of 1H-indazole-7-carbonitrile.
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.
Cottyn
Betty
B
Institut Lavoisier, CNRS UMR 8180, Université de Versailles, 45 Avenue des Etats Unis, 78035 Versailles cedex, France.
Acher
Francine
F
Ramassamy
Booma
B
Alvey
Luke
L
Lepoivre
Michel
M
Frapart
Yves
Y
Stuehr
Dennis
D
Mansuy
Daniel
D
Boucher
Jean-Luc
JL
Vichard
Dominique
D
D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D002460:Cell Line; D007191:Indazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000737:chemistry / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000737:chemistry; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D007191:Indazoles; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C080122:7-nitroindazole