Nitric oxide synthase inhibitor

2-cyano-3,12-dioxooleana-1,9(11 )-dien-28-oic acid triterpenoid (CDDO) derivatives have been prepared that suppress formation of inducible nitric oxide synthase (iNOS) in macrophages stimulated by interferon-7 in mouse macrophages. All the new triterpenoid derivatives are more potent than previously known CDDOs in treating conditions associated with inflammatory enzyme disorders. 

Preparation of tetra-0-acetyl-/8-D-glucopyranyl-2-cyano-3,12-dioxooleana-l,9(ll)-dien-28-ate (generic procedure for preparing oleananetriterpenoids esters) 

Selected triterpenoid ester derivatives are provided in Tables 1 and 2. 

9(1 l)-dien-28-oic derivatives. IC50 values between 0.01 and 1 pM level 

The inhibitory activities of selected experimental agents on iNO production induced by INF-y in mouse macrophages are provided in Tables 1 and 2. 

Hypoxia (0.2% O2, 6.2% CO2) inhibited the production of NO but did not affect the transcription of iNOS mRNA in rat smooth muscle cells treated with IFN-y, lipopolysaccharide, or both (Hong et al. 2000). 

Geldanamycin and 17-allylamino-17-demetho-xygeldanamycin both dose-dependently reduced nitrite accumulation, iNOS steady-state mRNA levels, and the cytokine-dependent activation of a rat 2.2-kB iNOS promoter construct stability expressed in rat glioma C6 cells (Murphy et al. 2002). 

The critical role played by the L-arginine/ NO pathway and the three major isoforms of NOS in regulating physiological and pathophysiological processes has induced significant efforts to develop isoform-selective NOS inhibitors. 

Parkinson (2000) reviewed the L-arginine-based substrate analogues, the most commonly used of 

N-Iminoethyl-L-ornithine (100 pM) significantly (P 0.05) decreased the capillary-like tube networks formed by human umbilical vein endothelial cells cultured on reconstituted basement membrane matrix Matrigel thus antagonising treatment with 

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Buisson, A., Margaill, L, Callebert, J., Plotkine, M. and Boulu, R.G. (1993). Mechanism involved in the neuroprotective activity of a nitric oxide synthase inhibitor during focal cerebral ischemia. J. Neurochem. 61, 690-696. 

Ribeiro, A. C. Kapas, L. (2005). Day- and nighttime injection of a nitric oxide synthase inhibitor elicits opposite sleep responses in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R521-31. 

Vazquez, J., Lydic, R. Baghdoyan, H. A. (2002). The nitric oxide synthase inhibitor NG-Nitro-L-arginine increases basal forebrain acetylcholine release during sleep and wakefulness. J. Neurosci. 22, 5597-605. 

Monti, J. M. Jantos, H. (2004). Microinjection of the nitric oxide synthase inhibitor L-NAME into the lateral basal forebrain alters the sleep/wake cycle of the rat. Prog. Neuropsychopharmacol. Biol Psychiatry 28 (2), 239-47. 

EI-Gohary M, Awara WM, Nassar S et al (1999) Deltamethrin-induced testicular apotosis in rats the protective effect of nitric oxide synthase inhibitor. Toxicology 132 1-8... 

Effect of a nitric oxide synthase inhibitor, S-ethylisothiourea, on cultured cells and cardiovascular functions of normal and lipopolysaccharide-treated rabbits, J. Biochem. (Tokyo) 119 (1996), p. 553-558... 

Tracey, W. R., Nakane, M., Basha, F., Carter, G., In vivo pharmacological evaluation of two novel type II (inducible) nitric oxide synthase inhibitors, Can. J. Physiol. Pharmacol. 73 (1995), p. 665-669... 

Mikawa, K., Kodama, S. I., Nishina, K., Obara, H., ONO-1714, a new inducible nitric oxide synthase inhibitor, attenuates diaphragmatic dysfunction associated with cerulein-induced pancreatitis in rats, Crit. Care Med. 29 (2001),... 

Naito, Y., Takagi, T., Ishikawa, T., Handa, O., Matsumoto, N., Yagi, N., Matsuyama, K., Yoshida, N., Yoshikawa, T., The inducible nitric oxide synthase inhibitor ONO-1714 blunts dextran sulfate sodium colitis in mice, Eur. ]. Pharmacol. 412 (2001), p.91-99... 

Z., Hart, S. L., Babbedge, R. C., Characterization of the novel nitric oxide synthase inhibitor 7-nitro indazole and related indazoles antinociceptive and cardiovascular effects, Br. J. Pharmacol. 110 (1993), p. 219-224... 

K. I. Hosoya, Y. Horibe, K. J. Kim, and V. H. Lee. Carrier-mediated transport of NG-nitro-L-arginine, a nitric oxide synthase inhibitor, in the pigmented rabbit conjunctiva. J Pharmacol Exp Ther 285 223-227 (1998)... 

Chiba, T., Bharucha, A.E., Thomforde, G.M., Kost, L.J., and Phillips, S.F., Model of rapid gastrointestinal transit in dogs effects of muscarinic antagonists and a nitric oxide synthase inhibitor, Neurogastroenterol. Motil., 14, 535, 2002. 

Wakefield, I.D., March, J.E., Kemp, P.A., Valentin, J.P., Bennett, T., and Gardiner, S.M., Comparative regional haemodynamic effects of the nitric oxide synthase inhibitors, S-methyl-L-thiocitrulline and L-NAME, in conscious rats, Br.J. Pharmacol., 39, 1235-1243, 2003. 

Ji, H.T., Stanton, B.Z., Igarashi, J., Li, H.Y., Martasek, P., Roman, L.J., Poulos, T.L., Silverman, R.B. Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors. J. Am. Chem. Soc. 2008, 130, 3900-14. 

Dunn R, Reed TA, Copeland PD, Frye CA (1998) The nitric oxide synthase inhibitor 7-nitroindazole displays enhanced anxiolytic efficacy without tolerance in rats following subchronic administration. Neuropharmacology 37 899-904 Freeman AR, Westphal J, Norris G, Roggero B, Webb P, Freeman K (1997) Efficacy of ondansetron in the treatment of generalized anxiety disorder. Depress Anxiety 5 140-141... 

The fluorescence properties of derivatives of oxazolo[4,5- ]pyridine has been reported by Mac et al. <2007JPP(A)188>. Martin et al. have reported the preparation of oxazolo[4,5- ]pyridine derivatives as inducible nitric oxide synthase inhibitors <2007W0045622>. 

Kolb, H., Kiesel, U., Kroncke, K-D., Kolb-Bachofen, V. (1991). Suppression of low dose streptozotocin induced diabetes in mice by administration of nitric oxide synthase inhibitor. Life Sci 49, PL213-PL217. 

Ashina, M. Nitric oxide synthase inhibitors for the treatment of chronic tension-type headache, Exp. Op. Pharm. 2002, 3, 395-399. 

Boer R., Ulrich, W.-R., Klein, T., Mirau, B., Haas, S., Baur, I. The Inhibitory potency and selectivity of arginine substrate site nitric-oxide synthase inhibitors is solely determined by their affinity toward the different isoenzymes, Mol. Pharmacol. 2000, 58, 1026-1034. 

Cheshire, D. R. Use of nitric oxide synthase inhibitors for the treatment of inflammatory disease and pain, IDrugs 2001, 4, 795-803. 

Durley, R., Sikorski, J., Hansen, D., Promo, M. A., Webber, R. K., Pitzele, B. S., Awasthi, A. K., Moorman, A. E. (Pharmacia Corporation) 2-Amino-2-alkyl-4-hexenoic and hexynoic acid derivatives useful as nitric oxide synthase inhibitors, WO 0222559. 

Lowe, J. A. Nitric oxide synthase inhibitors Recent patent activity, IDrugs 2000, 3, 63-72. 

Farooqui A. A. and Horrocks L. A. (1997). Nitric oxide synthase inhibitors do not attenuate diacylglycerol or monoacylglycerol lipase activities in synaptoneurosomes. Neurochem. Res. 22 1265-1269. 

Jewett D. C., Butelman E. R., and Woods J. H. (1996). Nitric oxide synthase inhibitors produce phencyclidine-like behavioral effects in pigeons. Brain Res. 715 25-31. 

Ribeiro AC, Gilligan JG, Kapas L. Systemic injection of a nitric oxide synthase inhibitor suppresses sleep responses to sleep deprivation in rats. Am J Physiol 2000 278 R1048-R1056. 

In contrast, noradrenergic sympathetic innervation of the airways is sparse, and these fibers do not appear to play a major role in controlling airway diameter. Bronchodilation may be brought about by nonadrenergic, noncholinergic nerves releasing nitric oxide since nitric oxide synthase inhibitors have been shown to reduce bronchodilation produced by electrical field stimulation in vitro. 

Martinez, J. A., Francis, G., Liu, W., Pradzin-sky, N., Fine, J., et al. (2008) Intranasal delivery of insulin and a nitric oxide synthase inhibitor in an experimental model of amyotrophic lateral sclerosis. Neuroscience. 

In summary, natural products have a few known general mechanisms of action. These include toxins, inhibitors of growth, surface-energy modifiers, nervous pathway interference (anesthetics, including nitric oxide synthase inhibitors and neurotransmitter blockers), inhibitors of attachment, inhibitors of metamorphosis, and repellants.46 55117118 It is likely that many compounds have multiple mechanisms of action. 

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