title: Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. synthesis and biological evaluation of dihydropyridin-2(1H)-imines and 1,5,6,7-tetrahydro-2H-azepin-2-imines.
abstract: The process of discovery and biological evaluation of alpha,beta-unsaturated cyclic amidines, as selective inhibitors of inducible nitric oxide synthase (iNOS), is reported. Dihydropyridin-2(1H)-imines and 1,5,6,7-tetrahydro-2H-azepin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide synthase inhibition assay. Compounds 1, 5, 6, 8-12 and 16 exhibited potent inhibition of iNOS. Among these, compounds 6, 7, 10, 11 and 16 showed 5- to 19-fold isoform selectivity. Compounds 1, 6, 10, 11 and 16 also showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 6 showed excellent bioavailability (BA) in rats when administered orally. Full details are presented here, including the structure-activity relationship (SAR) studies, the chemistry of these compounds, and the pharmacokinetic data and the computer-aided docking study of 10 with hiNOS.
authors.affiliation: Fukui Research Institute, Ono Pharmaceutical Co., Ltd., Technoport, Yamagishi, Mikuni, Sakai, Fukui 913-8538, Japan. kawanaka@ono.co.jp
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kawanaka
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Shinya
authors.initials: S
authors.lastname: Kusuda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Murota
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hisaichi
authors.forename: Atsuko
authors.initials: A
authors.lastname: Fujii
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hirai
authors.forename: Minoru
authors.initials: M
authors.lastname: Nishizaki
authors.forename: Masao
authors.initials: M
authors.lastname: Naka
authors.forename: Masaharu
authors.initials: M
authors.lastname: Komeno
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D000818:Animals; D001682:Biological Availability; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007097:Imines / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007097:Imines; D007202:Indicators and Reagents; D007527:Isoenzymes; D009566:Nitrates; D011725:Pyridines; D011994:Recombinant Proteins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat