title: Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase.
abstract: Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.
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: Maris A
authors.initials: MA
authors.lastname: Cinelli
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 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: Anthony V
authors.initials: AV
authors.lastname: Pensa
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: Soosung
authors.initials: S
authors.lastname: Kang
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 , Prague, Czech Republic.|BIOCEV , 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, 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: D000634:Aminoquinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D010647:Phenyl Ethers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D004791:Enzyme Inhibitors; D010647:Phenyl Ethers; C031538:phenyl ether; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III