Selective Inhibitors of Inducible Nitric Oxide Synthase: Potential Agents for the Treatment of Inflammatory Diseases?

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.

Treatment of Experimental Autoimmune Prostatitis in Nonobese Diabetic Mice by the Vitamin D Receptor Agonist Elocalcitol

“…In addition, a significantly decreased expression of iNOS, a key enzyme required for the synthesis of the inflammatory agent NO, and a markedly decreased production of NO itself, is observed in peritoneal macrophages from Elocalcitol-treated NOD mice with established EAP. A number of studies have associated excessive NO production with acute and chronic inflammation in model systems, and have also demonstrated that administration of NO synthase inhibitors can induce beneficial anti-inflammatory effects (58). The capacity of Elocalcitol to inhibit iNOS expression and NO production may thus represent an additional mechanism explaining its anti-inflammatory properties.…”

Selective probing of a NADPH site controlled light‐induced enzymatic catalysis

“…(Rod and Brooks, 2003;Wang et al, 2006;Chen et al, 2007;Mauldin et al, 2009) eNOS is an important pharmaceutical target, yet only the neuronal and inducible isoforms of NOS can be specifically inhibited, mainly at the level of their hemodomains. (Tinker and Wallace, 2006;Bonnefous et al, 2009;Silverman, 2009) The dihydrofolate reductase is a key enzyme in cell growth and metabolism. DHFR presents a large pharmacological interest and is the target of methotrexate used for treatments of cancer and infections.…”

Selective Acetamidine-Based Nitric Oxide Synthase Inhibitors: Synthesis, Docking, and Biological Studies

“…3 A third NOS isoform, inducible NOS (iNOS), plays an important role in the defense against pathogens and is expressed in several cells and tissues, including endothelial and vascular smooth muscle cells, 4 in response to pro-inflammatory stimuli such as bacterial endotoxins (LPS), and/or different cytokines and interleukins. 5 In contrast to the regulated production of NO by eNOS and nNOS, iNOS may generate large amounts of NO over long periods of time, if substrate and cofactors are not limited. 4 In the vascular system, the excessive amount of NO produced by iNOS is associated with decreased function of eNOS and subsequent impairment of both vasoconstriction and endothelium-dependent vasorelaxation.…”