title: Design and synthesis of inhibitors of inducible nitric oxide synthase. Discovery of a new chemical lead with potential for oral bioavailability.
abstract: A series of 2-iminopiperidines fused to small-membered rings (Tables 1 and 2) were synthesised and biologically evaluated using an in vitro human nitric oxide synthase (NOS) inhibition assay. Fused bicyclic compounds 5-9 exhibited nearly the same potency as compound 1 in the hiNOS inhibition assay. Among these, the 1-methyl analogues 8 and 9 showed better isoform selectivity than their corresponding unsubstituted analogues 7 and 6, respectively. Compounds 5 and 6 were also evaluated by an in vivo NO accumulation assay in a mouse model. The discovery process of new chemical leads for an orally bioavailable inhibitor of human inducible NOS (iNOS) is reported. The structure-activity relationship (SAR) study and chemistry of these compounds are also reported.
authors.affiliation: Fukui Research Institute, Ono Pharmaceutical Co. Ltd., Technoport, Yamagishi, Mikuni, Fukui 913-8538, Sakai, 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: 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; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; D010880:Piperidines; D011994:Recombinant Proteins; D019323:omega-N-Methylarginine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse