2-Iminohomopiperidinium Salts as Selective Inhibitors of Inducible Nitric Oxide Synthase (iNOS)

An attractive approach to the treatment of inflammatory conditions such as osteo- and rheumatoid arthritis, inflammatory bowel disease, and sepsis is through the selective inhibition of human inducible nitric oxide synthase (hiNOS) since localized excess nitric oxide (NO) release has been implicated...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1998-04, Vol.41 (9), p.1361-1366
Main Authors: Hansen, Donald W, Peterson, Karen B, Trivedi, Mahima, Kramer, Steven W, Webber, Ronald K, Tjoeng, Foe S, Moore, William M, Jerome, Gina M, Kornmeier, Christine M, Manning, Pamela T, Connor, Jane R, Misko, Thomas P, Currie, Mark G, Pitzele, Barnett S
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal - administration & dosage
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Azepines - administration & dosage
Azepines - chemical synthesis
Azepines - pharmacokinetics
Azepines - pharmacology
Biological and medical sciences
Biological Availability
Bones, joints and connective tissue. Antiinflammatory agents
Cell Line
Enzyme Induction - drug effects
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Humans
Imines - administration & dosage
Imines - chemical synthesis
Imines - pharmacokinetics
Imines - pharmacology
Inflammation - blood
Inflammation - chemically induced
Lipopolysaccharides - toxicity
Macrophages - drug effects
Macrophages - enzymology
Medical sciences
Mice
Nitric Oxide Synthase - antagonists & inhibitors
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Pharmacology. Drug treatments
Rats
Rats, Inbred Lew
Recombinant Proteins - chemical synthesis
Recombinant Proteins - pharmacology
Structure-Activity Relationship
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Summary:An attractive approach to the treatment of inflammatory conditions such as osteo- and rheumatoid arthritis, inflammatory bowel disease, and sepsis is through the selective inhibition of human inducible nitric oxide synthase (hiNOS) since localized excess nitric oxide (NO) release has been implicated in the pathology of these diseases. A series of monosubstituted iminohomopiperidinium salts possessing lipophilic functionality at ring positions 3, 5, 6, and 7 has been synthesized, and series members have demonstrated the ability to inhibit the hiNOS isoform with an IC50 as low as 160 nM (7). Compounds were found that selectively inhibit hiNOS over the human endothelial constitutive enzyme (heNOS) with a heNOS/hiNOS IC50 ratio in excess of 100 and as high as 314 (9). Potencies for inhibition of hiNOS and the human neuronal constitutive enzyme (hnNOS) are comparable. Substitution in the 3 and 7 positions provides compounds that exhibit the greatest degree of selectivity for hiNOS and hnNOS over heNOS. Submicromolar potencies for 6 and 7 in a mouse RAW cell assay demonstrated the ability of these compounds to inhibit iNOS in a cellular environment. These latter compounds were also found to be orally bioavailable and efficacious due to their ability to inhibit the increase in plasma nitrite/nitrate levels in a rat LPS model.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9704715