title: Bicyclic amidine inhibitors of nitric oxide synthase: discovery of perhydro-iminopyrindine and perhydro-iminoquinoline as potent, orally active inhibitors of inducible nitric oxide synthase.
abstract: Syntheses and nitric oxide synthase inhibitory activity of cyclic amidines containing 5,6- 6,6- and 7,6-fused systems are described. X-ray structure determination facilitated the assignment of the stereochemistry of the most active compounds perhydro-2-iminoisoquinoline (8a) and perhydro-2-iminopyrindine (10a). Both 8a and 10a are very potent inhibitors of iNOS, with excellent selectivity over eNOS and they are orally active in rats with long duration suitable for once or twice a day dosing.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Ravindra N
authors.initials: RN
authors.lastname: Guthikonda
authors.forename: Shrenik K
authors.initials: SK
authors.lastname: Shah
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Pacholok
authors.forename: John L
authors.initials: JL
authors.lastname: Humes
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mumford
authors.forename: Stephan K
authors.initials: SK
authors.lastname: Grant
authors.forename: Renee M
authors.initials: RM
authors.lastname: Chabin
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Green
authors.forename: Nancy
authors.initials: N
authors.lastname: Tsou
authors.forename: Richard
authors.initials: R
authors.lastname: Ball
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Fletcher
authors.forename: Silvi
authors.initials: S
authors.lastname: Luell
authors.forename: D
authors.initials: D
authors.lastname: Euan MacIntyre
authors.forename: Malcolm
authors.initials: M
authors.lastname: Maccoss
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000008:administration & dosage / Q000737:chemistry*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000737:chemistry*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry*; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats
chemical_list: D000578:Amidines; D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D011725:Pyridines; D011804:Quinolines; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat