Design and synthesis of inhibitors of inducible nitric oxide synthase. Discovery of a new chemical lead with potential for oral bioavailability |
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Authors: | Kawanaka Yasufumi Kobayashi Kaoru Kusuda Shinya Tatsumi Tadashi Murota Masayuki Nishiyama Toshihiko Hisaichi Katsuya Fujii Atsuko Hirai Keisuke Naka Masao Komeno Masaharu Nakai Hisao Toda Masaaki |
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Affiliation: | Fukui Research Institute, Ono Pharmaceutical Co. Ltd., Technoport, Yamagishi, Mikuni, Fukui 913-8538, Sakai, Japan. kawanaka@ono.co.jp |
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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. |
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