ChemInform Abstract: Inhibitors of Inducible NO Synthase Expression: Total Synthesis of (S)-Curvularin (Ia) and Its Ring Homologues (original) (raw)
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Inducible nitric oxide synthase inhibitors: A comprehensive update
Medicinal Research Reviews, 2019
Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. l‐Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non‐amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibit...
Journal of Clinical Investigation, 1995
We have recently put forward the hypothesis that the dual inhibition of proinflammatory nitric oxide (NO) and prostaglandins (PG) may contribute to the antiinflammatory properties of nitric oxide synthase (NOS) inhibitors. This hypothesis was tested in the present study. A rapid inflammatory response characterized by edema, high levels of nitrites (NOr, a breakdown product of NO), PG, and cellular infiltration into a fluid exudate was induced by the administration of carrageenan into the subcutaneous rat air pouch. The time course of the induction of inducible nitric oxide synthase (iNOS) protein in the pouch tissue was found to coincide with the production of NOR. Dexamethasone inhibited both iNOS protein expression and NO2synthesis in the fluid exudate (IC50 = 0.16 mg/kg). Oral administration of N-iminoethyl-L-lysine (L-NIL) or NG-nitro-L-arginine methyl ester (NO2Arg) not only blocked nitrite accumulation in the pouch fluid in a dose-dependent fashion but also attenuated the elevated release of PG. Finally, carrageenan administration produced a time-dependent increase in cellular infiltration into the pouch exudate that was inhibited by dexamethasone and NOS inhibitors. At early times, i.e., 6 h, the cellular infiltrate is composed primarily of neutrophils (98%). Pretreatment with colchicine reduced both neutrophil infiltration and leukotriene B4 accumulation in the air pouch by 98% but did not affect either NOor PG levels. In conclusion, the major findings of this paper are that (a) selective inhibitors of iNOS are clearly antiinflammatory agents by inhibiting not only NO but also PG and cellular infiltration and (b) that neutrophils are not responsible for high levels of NO and PG produced.
The Natural Product Noformycin Is an Inhibitor of Inducible-Nitric Oxide Synthase
Biochemical and Biophysical Research Communications, 1996
Inducible-Nitric oxide synthase (iNOS, EC 1.14.13.39) catalyzes the formation of nitric oxide (NO) and L-citrulline from L-Arg, NADPH and dioxygen. The natural product, (0)-noformycin was found to be a potent, competitive inhibitor of recombinant human iNOS with respect to L-Arg with a K i Å 1.3 { 0.3 mM. The reversible binding of noformycin caused a high spin type I spectral perturbation of the iNOS heme group with a K d Å 1.5 { 0.2 mM. These results demonstrate that natural products may be a useful source for inhibitors of NO-biosynthesis. ᭧
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.
A synthetic curcuminoid derivative inhibits nitric oxide and proinflammatory cytokine synthesis
European Journal of Pharmacology, 2010
Curcumin is a highly pleiotropic molecule with significant regulatory effects upon inflammation and inflammatory related diseases. However curcumin has one major important limitation in which it has poor bioavailability. Design of synthetic structural derivatives of curcumin is but one approach that has been used to overcome its poor bioavailability while retaining, or further enhancing, its drug-like effects. We have synthesized a series of curcumin analogues and describe the effects of 2,6-bis-4-(hydroxyl-3-methoxybenzylidine)-cyclohexanone or BHMC upon nitric oxide and cytokine synthesis in cellular models of inflammation. BHMC showed a significant dose-response inhibitory action upon the synthesis of NO and we have shown that this effect was due to suppression of both iNOS gene and enzyme expression without any effects upon scavenging of nitrite. We also demonstrated that BHMC has a very minimal effect upon iNOS activity with no effect at all upon the secretion of PGE 2 but has a strong inhibitory effect upon MCP-1 and IL-10 secretion and gene expression. Secretion and gene expression of TNF-α and IL-6 were moderately inhibited whereas IL-8 and IL-1β were not altered. We conclude that BHMC selectively inhibits the synthesis of several inflammatory mediators. BHMC should be considered a promising drug lead for preclinical and further pharmacological studies.
Isothioureas: potent inhibitors of nitric oxide synthases with variable isoform selectivity
British Journal of Pharmacology, 1995
1 The induction of a calcium-independent isoform of nitric oxide (NO) synthase (iNOS) and a subsequent enhanced formation of NO has been implicated in the pathophysiology of a variety of diseases including inflammation and circulatory shock. Here we demonstrate that the S-substituted isothioureas, S-methylisothiourea (SMT), S-(2-aminoethyl)isothiourea (aminoethyl-TU), Sethylisothiourea (ethyl-TU) and S-isopropylisothiourea (isopropyl-TU) potently inhibit iNOS activity in J774.2 macrophages activated with bacterial endotoxin with EC50 values 8-24 times lower than that of N0-methyl-L-arginine (MeArg) and 200-times lower than that of NG-nitro-L-arginine (L-NO2Arg). 2 The inhibition of iNOS activity by these S-substituted isothioureas is dose-dependently prevented by excess of L-arginine suggesting that these isothioureas are competitive inhibitors of iNOS at the L-arginine binding site. 3 Ethyl-TU and isopropyl-TU are 4-6 times more potent than MeArg in inhibiting the constitutive NOS activity in homogenates of bovine aortic endothelial cells (eNOS) and are more potent pressor agents than MeArg in the anaesthetized rat. SMT is equipotent with MeArg, whereas aminoethyl-TU is 6-times less potent in inhibiting eNOS activity in vitro. Both SMT and aminoethyl-TU, however, elicit only weak pressor responses (approximately 15 mmHg at 10mg kg-', i.v.) in vivo. 4 A comparison of the potencies of ethyl-, iso-propyl-, n-propyl-, t-butyland n-butyl-isothioureas on iNOS activity shows that the inhibitory activity of S-substituted isothioureas declines sharply if the side chain exceeds 2 carbon atoms in length. Similarly, substitution of the ethylene side chain of ethyl-TU also results in a diminished potency. Substitution of either one or both nitrogens of SMT with either amino or alkyl groups also substantially reduces its NOS inhibitory potency. 5 In conclusion, isothioureas represent a new class of NOS inhibitors which includes the most potent inhibitors of iNOS activity reported to date. Some members of this class (ethyl-TU and isopropyl-TU) are potent inhibitors of eNOS and iNOS with little selectivity towards either isoform, while others (SMT and aminoethyl-TU) are relatively selective inhibitors of iNOS activity. These latter agents may become useful tools for studying the role of iNOS in various disease models and may be useful in the therapy of diseases that are associated with an enhanced formation of NO due to iNOS induction, such as inflammation, circulatory shock or cancer.
Advances in Design and Development of Inhibitors of Nitric Oxide Synthases
Nitric oxide synthase (NOS) is a dimeric enzyme that catalyses the production of nitric oxide (NO) in the human body. The nitric oxide has been identified as the most interesting and vital mediators for normal and pathological processes, including the regulation of blood pressure, neurotransmission, and macrophage defence system, but the over production of it can be toxic, hence their inhibitors are desired. In this article, the various isoforms of NOS and their roles are described and a detail of the development of their inhibitors has been presented. The inhibitors studied include aminopyridines, iminopiperidines, N-phenylamidines, benzoxazolones, isothioureas, oxazepanes, thiazepanes, diazepanes, 4,5-disubstituted-1,3-oxazolidin-2-imine derivatives, thiazolidines, pyrazoles, pyrazolines, and some others
Molecular pharmacology, 2003
The induction of human inducible nitric-oxide synthase (iNOS) expression depends (among other factors) on activation of the signal transducer and activator of transcription 1 (STAT1) pathway. Therefore, the STAT1 pathway may be an appropriate target for the development of inhibitors of iNOS expression. HeLa S3 cells transiently transfected with a gamma-activated site (GAS)/interferon-stimulated response element-driven reporter gene construct were used as the primary screening system. Using this system, three novel inhibitors of interferon-gamma-dependent gene expression, namely, sporogen, S14-95, and S-curvularin, were isolated from different Penicillium species. These three compounds also inhibited cytokine-induced, GAS-dependent reporter gene expression in stably transfected human A549/8-pGASLuc cells, confirming the data obtained with the above-mentioned screening system. Furthermore, in A549/8 cells, sporogen, S14-95, and S-curvularin inhibited cytokine-induced activity of the h...