Inducible nitric oxide synthase inhibitors: A comprehensive update (original) (raw)
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Novel Nitric Oxide Synthase (NOS) Inhibitors: a Patent Review
2014
Introduction: Knowledge of nitric oxide and its function in cell signaling has rapidly developed since its first biological effects were described in 1977. It is formed from L-arginine by nitric oxide synthase isoforms (nNOS, iNOS and eNOS). These enzymes are products of separate genes, encoded on three different chromosomes and responsible for regulating a variety of functions within cells and tissues, which include vasodilatation, neurotransmission and the immunological process. NOS isoforms are currently under investigation as targets for novel therapeutics in especially neurodegenerative disorders, inflammation and· pain. Many important questions regarding the formation, function and metabolism of these important messengers and signaling molecules remain to be answered. Areas covered in this review: This review gives an overview of patents covering drug-like inhibitors for the NOS isoforms filed and published within the last 6 years, up to September 2010, as well as insight into...
Inducible nitric oxide synthase: Good or bad?
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2017
Nitric oxide synthases (NOS) are a family of isoforms responsible for the synthesis of the potent dilator nitric oxide (NO). Expression of inducible NOS (iNOS) occurs in conditions of inflammation, and produces large amounts of NO. In pathological conditions iNOS is regarded as a harmful enzyme and is proposed to be a major contributor to diseases of the cardiovascular system such as atherosclerosis. In this review, we address the notion that iNOS is a detrimental enzyme in disease and discuss its potentially beneficial roles. Additionally, we describe other molecules associated with iNOS in diseases such as atherosclerosis, and current research on therapeutic inhibitors tested to reduced pathology associated with cardiovascular diseases (CVD).
Role of nitric oxide in inflammatory diseases
Inflammopharmacology, 2007
Nitric oxide (NO) is a signaling molecule that plays a key role in the pathogenesis of infl ammation. It gives an anti-infl ammatory effect under normal physiological conditions. On the other hand, NO is considered as a pro-infl ammatory mediator that induces infl ammation due to over production in abnormal situations. NO is synthesized and released into the endothelial cells by the help of NOSs that convert arginine into citrulline producing NO in the process. Oxygen and NADPH are necessary co-factors in such conversion. NO is believed to induce vasodilatation in cardiovascular system and furthermore, it involves in immune responses by cytokine-activated macrophages, which release NO in high concentrations. In addition, NO is a potent neurotransmitter at the neuron synapses and contributes to the regulation of apoptosis. NO is involved in the pathogenesis of infl ammatory disorders of the joint, gut and lungs. Therefore, NO inhibitors represent important therapeutic advance in the management of infl ammatory diseases. Selective NO biosynthesis inhibitors and synthetic arginine analogues are proved to be used for the treatment of NO-induced infl ammation. Finally, the undesired effects of NO are due to its impaired production, including in short: vasoconstriction, infl ammation and tissue damage.
Arginine-Based Inhibitors of Nitric Oxide Synthase: Therapeutic Potential and Challenges
Mediators of Inflammation, 2012
In the past three decades, nitric oxide has been well established as an important bioactive molecule implicated in regulation of cardiovascular, nervous, and immune systems. Therefore, it is not surprising that much effort has been made to find specific inhibitors of nitric oxide synthases (NOS), the enzymes responsible for production of nitric oxide. Among the many NOS inhibitors developed to date, inhibitors based on derivatives and analogues of arginine are of special interest, as this category includes a relatively high number of compounds with good potential for experimental as well as clinical application. Though this group of inhibitors covers early nonspecific compounds, modern drug design strategies such as biochemical screening and computer-aided drug design have provided NOS-isoform-specific inhibitors. With an emphasis on major advances in this field, a comprehensive list of inhibitors based on their structural characteristics is discussed in this paper. We provide a sum...
British Journal of Pharmacology, 2005
1 GW274150 ([2-[(1-iminoethyl) amino]ethyl]-L-homocysteine) and GW273629 (3-[[2-[(1-iminoethyl) amino]ethyl]sulphonyl]-L-alanine) are potent, time-dependent, highly selective inhibitors of human inducible nitric oxide synthase (iNOS) vs endothelial NOS (eNOS) (4100-fold) or neuronal NOS (nNOS) (480-fold). GW274150 and GW273629 are arginine competitive, NADPH-dependent inhibitors of human iNOS with steady state K d values of o40 and o90 nM, respectively. 2 GW274150 and GW273629 inhibited intracellular iNOS in J774 cells in a time-dependent manner, reaching IC 50 values of 0.270.04 and 1.370.16 mM, respectively. They were also acutely selective in intact rat tissues: GW274150 was 4260-fold and 219-fold selective for iNOS against eNOS and nNOS, respectively, while GW273629 was 4150-fold and 365-fold selective for iNOS against eNOS and nNOS, respectively. 3 The pharmacokinetic profile of GW274150 was biphasic in healthy rats and mice with a terminal half-life of B6 h. That of GW273629 was also biphasic in rats, producing a terminal half-life of B3 h. In mice however, elimination of GW273629 appeared monophasic and more rapid (B10 min). Both compounds show a high oral bioavailability (490%) in rats and mice. 4 GW274150 was effective in inhibiting LPS-induced plasma NO x levels in mice with an ED 50 of 3.270.7 mg kg À1 after 14 h intraperitoneally (i.p.) and 3.871.5 mg kg À1 after 14 h when administered orally. GW273629 showed shorter-lived effects on plasma NO x and an ED 50 of 972 mg kg À1 after 2 h when administered i.p. 5 The effects of GW274150 and GW273629 in vivo were consistent with high selectivity for iNOS, as these inhibitors were of low potency against nNOS in the rat cerebellum and did not cause significant effects on blood pressure in instrumented mice.
Proceedings of the National Academy of Sciences, 2000
Potent and selective inhibitors of inducible nitric oxide synthase (iNOS) (EC 1.14.13.39) were identified in an encoded combinatorial chemical library that blocked human iNOS dimerization, and thereby NO production. In a cell-based iNOS assay (A-172 astrocytoma cells) the inhibitors had low-nanomolar IC 50 values and thus were >1,000-fold more potent than the substrate-based direct iNOS inhibitors 1400W and N-methyl-L-arginine. Biochemical studies confirmed that inhibitors caused accumulation of iNOS monomers in mouse macrophage RAW 264.7 cells. High affinity (Kd Ϸ 3 nM) of inhibitors for isolated iNOS monomers was confirmed by using a radioligand binding assay. Inhibitors were >1,000-fold selective for iNOS versus endothelial NOS dimerization in a cellbased assay. The crystal structure of inhibitor bound to the monomeric iNOS oxygenase domain revealed inhibitor-heme coordination and substantial perturbation of the substrate binding site and the dimerization interface, indicating that this small molecule acts by allosterically disrupting protein-protein interactions at the dimer interface. These results provide a mechanism-based approach to highly selective iNOS inhibition. Inhibitors were active in vivo, with ED 50 values of <2 mg͞kg in a rat model of endotoxininduced systemic iNOS induction. Thus, this class of dimerization inhibitors has broad therapeutic potential in iNOS-mediated pathologies.