title: Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. Part 1: synthesis and biological evaluation of dihydropyridin-2-imines.
abstract: Dihydropyridin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide inhibition assay. Compounds 1, 4, 5 and 7-11 exhibited potent activity in the inducible nitric oxide (iNOS) inhibition assay. Of these 5, 6, 9 and 10 showed 5- to 11-fold increases in isoform selectivity. Compounds 1, 5, 9 and 10 showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 5 also showed good bioavailability (BA) when given orally.
authors.affiliation: Fukui Research Institute, Ono Pharmaceutical Co., Ltd., Technoport, Yamagishi, Mikuni, Sakai, Fukui, 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: Masanori
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: 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: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D007097:Imines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D020714:Maximum Tolerated Dose; D051379:Mice; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D013329:Structure-Activity Relationship
chemical_list: D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D007097:Imines; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse