title: Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase.
abstract: In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) versus (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF(2) moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a K(i) of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pK(a) NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compound to the parent molecule shows 22% for the difluorinated compound versus essentially no oral bioavailability for the parent compound. This indicates that the goal of this research to make compounds with only one protonated nitrogen atom at physiological pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished.
authors.affiliation: Department of Chemistry and Biochemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, USA.
authors.forename: Fengtian
authors.initials: F
authors.lastname: Xue
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Delker
authors.forename: Jianguo
authors.initials: J
authors.lastname: Fang
authors.forename: Pavel
authors.initials: P
authors.lastname: Martásek
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Roman
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008958:Models, Molecular; D015394:Molecular Structure; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D052248:Nitric Oxide Synthase Type I