title: New hypotheses for the binding mode of 4- and 7-substituted indazoles in the active site of neuronal nitric oxide synthase.
abstract: Taking into account the potency of 4- and 7-nitro and haloindazoles as nNOS inhibitors previously reported in the literature by our team, a multidisciplinary study, described in this article, has recently been carried out to elucidate their binding mode in the enzyme active site. Firstly, nitrogenous fastening points on the indazole building block have been investigated referring to molecular modeling hypotheses and thanks to the in vitro biological evaluation of N(1)- and N(2)-methyl and ethyl-4-substituted indazoles on nNOS. Secondly, we attempted to confirm the importance of the substitution in position 4 or 7 by a hydrogen bond acceptor group thanks to the synthesis and the in vitro biological evaluation of a new analogous 4-substituted derivative, the 4-cyanoindazole. Finally, by opposition to previous hypotheses describing NH function in position 1 of the indazole as a key fastening point, the present work speaks in favour of a crucial role of nitrogen in position 2.
authors: Université de Caen Basse-Normandie, EA-4258 CERMN, FR CNRS 3038 INC3M, SF 4206 ICORE, UFR des Sciences Pharmaceutiques, Boulevard Becquerel, F-14032 Caen, France.
authors: Elodie
authors: E
authors: Lohou
authors: Jana
authors: J
authors: Sopkova-de Oliveira Santos
authors: Pascale
authors: P
authors: Schumann-Bard
authors: Michel
authors: M
authors: Boulouard
authors: Silvia
authors: S
authors: Stiebing
authors: Sylvain
authors: S
authors: Rault
authors: Valérie
authors: V
authors: Collot
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D052248:Nitric Oxide Synthase Type I