title: Recent advances toward improving the bioavailability of neuronal nitric oxide synthase inhibitors.
abstract: Overproduction of nitric oxide by neuronal nitric oxide synthase (nNOS) has been highly correlated with numerous neurodegenerative diseases and stroke. Given its role in human diseases, nNOS is an important target for therapy that deserves further attention. During the last decade, a large number of organic scaffolds have been investigated to develop selective nNOS inhibitors, resulting in two principal classes of compounds, 2-aminopyridines and thiophene-2- carboximidamides. The former compounds were investigated in detail by our group, exhibiting great potency and excellent selectivity; however, they suffer from poor bioavailability, which hampers their therapeutic potential. Here we present a review of various strategies adopted by our group to improve the bioavailability of 2-aminopyridine derivatives and describe recent advances in thiophene-2-carboximidamide based nNOS-selective inhibitors, which exhibit promising pharmacological profiles.
authors.affiliation: Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000818:Animals; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D052248:Nitric Oxide Synthase Type I