Abstract
Nitric Oxide (NO) is widely recognized as an important messenger and effector molecule in a variety of biological systems. There is strong evidence from animal models that elevated or lowered NO levels are associated with a variety of pathological states. In nature, NO is synthesised from the amino acid L-arginine by a small family of closely related oxygenase enzymes: the nitric oxide synthases (NOS). A number of studies in animals have associated excessive NO production by one of these enzymes - the inducible NOS isoform (iNOS or NOS-II) - with acute and chronic inflammation in model systems and have also demonstrated that administration of NOS inhibitors can produce beneficial effects. Regrettably, however, the relatively poor potency, selectivity and pharmacokinetic (ADME) profiles of the available inhibitors have so far precluded a convincing demonstration of their efficacy in the clinic. This review will describe the current state of knowledge of the structure and function of NOS and the various approaches that are being followed in the search for truly selective NOS inhibitors as therapeutic agents for inflammatory diseases.
Keywords: cGMP, phosphorylation, Crystallography, physicochemical properties, Guanidine, Simple carbamidines, cofactors
Current Topics in Medicinal Chemistry
Title: Selective Inhibitors of Inducible Nitric Oxide Synthase: Potential Agents for the Treatment of Inflammatory Diseases?
Volume: 6 Issue: 2
Author(s): Alan C. Tinker and Alan V. Wallace
Affiliation:
Keywords: cGMP, phosphorylation, Crystallography, physicochemical properties, Guanidine, Simple carbamidines, cofactors
Abstract: Nitric Oxide (NO) is widely recognized as an important messenger and effector molecule in a variety of biological systems. There is strong evidence from animal models that elevated or lowered NO levels are associated with a variety of pathological states. In nature, NO is synthesised from the amino acid L-arginine by a small family of closely related oxygenase enzymes: the nitric oxide synthases (NOS). A number of studies in animals have associated excessive NO production by one of these enzymes - the inducible NOS isoform (iNOS or NOS-II) - with acute and chronic inflammation in model systems and have also demonstrated that administration of NOS inhibitors can produce beneficial effects. Regrettably, however, the relatively poor potency, selectivity and pharmacokinetic (ADME) profiles of the available inhibitors have so far precluded a convincing demonstration of their efficacy in the clinic. This review will describe the current state of knowledge of the structure and function of NOS and the various approaches that are being followed in the search for truly selective NOS inhibitors as therapeutic agents for inflammatory diseases.
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Cite this article as:
Tinker C. Alan and Wallace V. Alan, Selective Inhibitors of Inducible Nitric Oxide Synthase: Potential Agents for the Treatment of Inflammatory Diseases?, Current Topics in Medicinal Chemistry 2006; 6 (2) . https://dx.doi.org/10.2174/156802606775270297
DOI https://dx.doi.org/10.2174/156802606775270297 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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