1. Design and synthesis of inhibitors of inducible nitric oxide synthase. Discovery of a new chemical lead with potential for oral bioavailability.
- Author
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Kawanaka Y, Kobayashi K, Kusuda S, Tatsumi T, Murota M, Nishiyama T, Hisaichi K, Fujii A, Hirai K, Naka M, Komeno M, Nakai H, and Toda M
- Subjects
- Administration, Oral, Animals, Biological Availability, Drug Design, Enzyme Inhibitors toxicity, Humans, Indicators and Reagents, Isoenzymes antagonists & inhibitors, Kinetics, Mice, Mice, Inbred BALB C, Nitric Oxide Synthase Type II, Recombinant Proteins drug effects, Structure-Activity Relationship, Substrate Specificity, omega-N-Methylarginine pharmacology, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Nitric Oxide Synthase antagonists & inhibitors, Piperidines chemical synthesis, Piperidines pharmacology
- 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.
- Published
- 2003
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