Selective Inhibitors of Inducible Nitric Oxide Synthase: Potential Agents for the Treatment of Inflammatory Diseases?
Alan C. Tinker and Alan V. Wallace
Affiliation: Department of DiscoveryBioscience, AstraZeneca R Charnwood, Bakewell Road, Loughborough,Leics LE11 5RH, England.
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
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