title: An Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors.
abstract: The three important mammalian isozymes of nitric oxide synthase (NOS) are neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Inhibitors of nNOS show promise as treatments for neurodegenerative diseases. Eight easily-synthesized compounds containing either one (20a,b) or two (9a-d; 15a,b) 2-amino-4-methylpyridine groups with a chiral pyrrolidine linker were designed as selective nNOS inhibitors. Inhibitor9cis the best of these compounds, having a potency of 9.7 nM and dual selectivity of 693 and 295 against eNOS and iNOS, respectively. Crystal structures of nNOS complexed with either9aor9cshow a double-headed binding mode, where each 2-aminopyridine head group interacts with either a nNOS active site Glu residue or a heme propionate. In addition, the pyrrolidine nitrogen of9ccontributes additional hydrogen bonds to the heme propionate, resulting in a unique binding orientation. In contrast, the lack of hydrogen bonds from the pyrrolidine of9ato the heme propionate allows the inhibitor to adopt two different binding orientations. Both9aand9cbind to eNOS in a single-headed mode, which is the structural basis for the isozyme selectivity.
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jing
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, California 92697-3900, USA.
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry, The University of Texas Health Science Center, San Antonio, TX 78384-7760, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Roman
authors.affiliation: Department of Biochemistry, The University of Texas Health Science Center, San Antonio, TX 78384-7760, USA ; Department of Pediatrics, First Faculty of Medicine, Charles University, Prague, 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, USA.
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, Evanston, Illinois 60208-3113, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
keywords: enzyme inhibition; neurodegenerative diseases; nitric oxide; nitric oxide synthase