title: In search of potent and selective inhibitors of neuronal nitric oxide synthase with more simple structures.
abstract: In certain neurodegenerative diseases damaging levels of nitric oxide (NO) are produced by neuronal nitric oxide synthase (nNOS). It, therefore, is important to develop inhibitors selective for nNOS that do not interfere with other NOS isoforms, especially endothelial NOS (eNOS), which is critical for proper functioning of the cardiovascular system. While we have been successful in developing potent and isoform-selective inhibitors, such as lead compounds 1 and 2, the ease of synthesis and bioavailability have been problematic. Here we describe a new series of compounds including crystal structures of NOS-inhibitor complexes that integrate the advantages of easy synthesis and good biological properties compared to the lead compounds. These results provide the basis for additional structure-activity relationship (SAR) studies to guide further improvement of isozyme selective inhibitors.
authors.affiliation: Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jing
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.forename: Jianguo
authors.initials: J
authors.lastname: Fang
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Roman
authors.forename: Pavel
authors.initials: P
authors.lastname: Martásek
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C587055:6-((3-(((3-fluorophenethyl)amino)methyl)phenoxy)methyl)-4-methylpyridin-2-amine; D000631:Aminopyridines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III
keywords: Aminopyridines; Inhibition; Neuronal nitric oxide synthase; Nitric oxide