title: Cell-permeable inhibitors of neuronal nitric oxide synthase open new prospects for the treatment of neurological disorders.
abstract: The disubstituted pyrimidines based SAR study by Silverman et al. ( J. Med. Chem. 2014 , DOI: 10.1021/jm501719e ) was focused on improving bioavailability and physicochemical properties of the designed inhibitors while retaining the potency for neural nitric oxide synthase (nNOS) and selectivity over the other two nitric oxide synthase (NOS) isoforms (endothelial NOS and inducible NOS). One of the new promising lead compounds, compound 7, displayed nanomolar potency for nNOS (Ki = 19 nM), good selectivity over endothelial (260-fold), and inducible (41-fold) NOS isoforms and also showed potential for oral bioavailability (good cell permeability with efflux ratio of 1.8) and broad safety profile with minimal off-target activities at 50 CNS based receptors. This remarkable achievement not only serves as a template for next generation selective NOS inhibitor design but also opens new prospects for the treatment of neurological disorders.
authors.affiliation: Vibrant Pharma Inc. , 45 Dalkeith Drive, Unit 14, Brantford, Ontario, N3P 1M1, Canada.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Annedi
mesh_terms: D002463:Cell Membrane Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D015394:Molecular Structure; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D052248:Nitric Oxide Synthase Type I