title: Improved synthesis of chiral pyrrolidine inhibitors and their binding properties to neuronal nitric oxide synthase.
abstract: We report an efficient synthetic route to chiral pyrrolidine inhibitors of neuronal nitric oxide synthase (nNOS) and crystal structures of the inhibitors bound to nNOS and to endothelial NOS. The new route enables versatile structure-activity relationship studies on the pyrrolidine-based scaffold, which can be beneficial for further development of nNOS inhibitors. The X-ray crystal structures of five new fluorine-containing inhibitors bound to nNOS provide insights into the effect of the fluorine atoms on binding.
authors.affiliation: Departments of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113, USA.
authors.forename: Fengtian
authors.initials: F
authors.lastname: Xue
authors.forename: James M
authors.initials: JM
authors.lastname: Kraus
authors.forename: Kristin Jansen
authors.initials: KJ
authors.lastname: Labby
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Jan
authors.initials: J
authors.lastname: Mataka
authors.forename: Guoyao
authors.initials: G
authors.lastname: Xia
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Delker
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: D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011759:Pyrrolidines; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III