Substituted 2-Iminopiperidines as Inhibitors of Human Nitric Oxide Synthase Isoforms

A series of analogues of 2-iminopiperidine have been prepared and shown to be potent inhibitors of the human nitric oxide synthase (NOS) isoforms. Methyl substitutions on the 4-position (3) or 4- and 6-positions (8) afforded the most potent analogues. These compounds exibited IC50 values of 0.1 and...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1998-01, Vol.41 (1), p.96-101
Main Authors: Webber, R. Keith, Metz, Suzanne, Moore, William M, Connor, Jane R, Currie, Mark G, Fok, Kam F, Hagen, Timothy J, Hansen, Donald W, Jerome, Gina M, Manning, Pamela T, Pitzele, Barnett S, Toth, Mihaly V, Trivedi, Mahima, Zupec, Mark E, Tjoeng, F. Siong
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Cerebellum - enzymology
Endothelium, Vascular - enzymology
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Imines - chemical synthesis
Imines - chemistry
Imines - pharmacology
Isoenzymes - antagonists & inhibitors
Kinetics
Lipopolysaccharides - pharmacology
Male
Medical sciences
Molecular Structure
Neurons - enzymology
Nitrates - blood
Nitric Oxide Synthase - antagonists & inhibitors
Nitrites - blood
Pharmacology. Drug treatments
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Rats
Rats, Inbred Lew
Recombinant Proteins - antagonists & inhibitors
Structure-Activity Relationship
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Description
Summary:A series of analogues of 2-iminopiperidine have been prepared and shown to be potent inhibitors of the human nitric oxide synthase (NOS) isoforms. Methyl substitutions on the 4-position (3) or 4- and 6-positions (8) afforded the most potent analogues. These compounds exibited IC50 values of 0.1 and 0.08 μM, respectively, for hiNOS inhibition. Substitution with cyclohexylmethyl at the 6-position (13) afforded an inhibitor that showed the best selectivity for hiNOS versus heNOS (heNOS IC50/hiNOS IC50 = 64). Following oral administration, inhibitors were found to decrease serum nitrite/nitrate levels in an in vivo rat endotoxin assay. This series of 2-iminopiperidines were prepared via the described synthetic methodologies. The effect of ring substitutions on potency and selectivity for this class of cyclic amidines as NOS inhibitors is described.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9705059