title: Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker.
abstract: Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability.
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
authors.forename: Heng-Yen
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.|State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University , Nanjing 210093, People's Republic of China.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California , Irvine, California 92697-3900, United States.
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center , San Antonio, Texas 78384-7760, United States.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Roman
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center , San Antonio, Texas 78384-7760, United States.|Department of Pediatrics, First Faculty of Medicine, Charles University , 121 08 Prague, Czech Republic.|BIOCEV , 252 42 Vestec, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Martásek
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California , Irvine, California 92697-3900, United States.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D052248:Nitric Oxide Synthase Type I; C032439:alpha-aminopyridine