title: Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS): synthesis and biological evaluation.
abstract: In order to find new compounds with neuroprotective activity and NOS-I/NOS-II selectivity, we have designed, synthesized, and characterized 14 new NOS inhibitors with an indazole structure. The first group corresponds to 4,5,6,7-tetrahydroindazoles (4-8), the second to the N-methyl derivatives (9-12) of 7-nitro-1H-indazole (1) and 3-bromo-7-nitro-1H-indazole (2), and the latter to 4,5,6,7-tetrafluoroindazoles (13-17). Compound 13 (4,5,6,7-tetrafluoro-3-methyl-1H-indazole) inhibited NOS-I by 63% and NOS-II by 83%. Interestingly, compound 16 (4,5,6,7-tetrafluoro-3-perfluorophenyl-1H-indazole) inhibited NOS-II activity by 80%, but it did not affect to NOS-I activity. Structural comparison between these new indazoles further supports the importance of the aromatic indazole skeleton for NOS inhibition and indicate that bulky groups or N-methylation of 1 and 2 diminish their effect on NOS activity. The fluorination of the aromatic ring increased the inhibitory potency and NOS-II selectivity, suggesting that this is a promising strategy for NOS selective inhibitors.
authors.affiliation: Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain. rclaramunt@ccia.uned.es
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Claramunt
authors.forename: Concepción
authors.initials: C
authors.lastname: López
authors.forename: Carlos
authors.initials: C
authors.lastname: Pérez-Medina
authors.forename: Marta
authors.initials: M
authors.lastname: Pérez-Torralba
authors.forename: José
authors.initials: J
authors.lastname: Elguero
authors.forename: Germaine
authors.initials: G
authors.lastname: Escames
authors.forename: Darío
authors.initials: D
authors.lastname: Acuña-Castroviejo
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054879:Halogenation; D006418:Heme / Q000737:chemistry; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D018696:Neuroprotective Agents; D006418:Heme; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II