Synthesis, pharmacological study and modeling of 7-methoxyindazole and related substituted indazoles as neuronal nitric oxide synthase inhibitors.
The synthesis, pharmacological evaluation and modelisation of 7-methoxyindazole (7-MI) and related alkoxyindazoles as novel inhibitors of neuronal nitric oxide synthase are presented. 7-MI remains the most active compound of this series in an in vitro enzymatic assay of neuronal nitric oxide synthase activity. Modeling studies of the interaction of 7-substituted indazole derivatives complexed with nNOS and the relationship with their respective biological activities suggest that a bulky substitution on position-7 is responsible for a steric hindrance effect which does not allow these compounds to interact with nNOS in the same way as 7-NI and 7-MI.
Collot
Valérie
V
UPRES-EA 2126--Centre d'Etudes et de Recherche sur le Médicament de Normandie--UFR Sciences Pharmaceutiques, 5 rue Vaubénard, 14032 Caen, France.
Sopkova-de Oliveira Santos
Jana
J
Schumann-Bard
Pascale
P
Colloc'h
Nathalie
N
Mackenzie
Eric T
ET
Rault
Sylvain
S
D000818:Animals; D002531:Cerebellum / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D013329:Structure-Activity Relationship
C436345:7-methoxyindazole; D004791:Enzyme Inhibitors; D007191:Indazoles; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat