INOS inhibitors

Normally corticosteroids are used for COPD treatment. The corticosteroids bind to glucocorticoid receptors and enter the nucleus of the cells, where it recruits HDAC-2. HDAC-2 deacetylates the chromatin and represses gene expression of inflammatory genes. Thus, low levels of HDAC-2 is detrimental to the treatment of COPD. Antioxidants (for removal of superoxides) or iNOS inhibitor or theophylline/curcumin for PI3K inhibition are some of the options to restore the required HDAC-2 level. 

Prostaglandins (PG) and nitric oxide (NO) produced by inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS), respectively, have been implicated as important mediators in the processes of inflammation and carcinogenesis. Potential COX-2 and iNOS inhibitors have been considered as anti-inflammatory and cancer chemopreventive agents [25]. 

Fluorinated amino acids, (VI), and hexynoic derivatives, (VII), prepared by Durley (3) were effective as iNOS inhibitors and used in the treatment of epithelial cell-derived neoplasia. 

The role of hepatic-inducible nitric oxide synthase (iNOS) has been investigated in the rat and in the mouse. Gardner and coworkers (Gardner et al. 1998) reported that toxic doses of acetaminophen to rats induced iNOS in the centrilobular hepatocytes. The development of toxicity correlated with the expression of iNOS. Moreover, treatment of rats with the iNOS inhibitor, aminoguanidine, decreased hepatotoxicity. The role of iNOS in the progression of acetaminophen toxicity was evaluated in iNOS knockout mice. Whereas ALT levels in acetaminophen-treated iNOS knockout mice were approximately 50% of those observed in wild-type mice,... 

Human bronchial epithelial cells stimulated with 50ng/ml interleukin-ip, tumour necrosis factor-a, and interferon-y express iNOS mRNA, protein and increased nitrite in the cell culture media, which was inhibited by the selective iNOS inhibitor 1400W (Donnelly and Barnes 2002). Cells derived from patients with asthma produced less nitrite than cells from normal subjects (6.59 0.99 pM nitrite, n = 15 versus 3.89 0.42 pM nitrite, n = 20 P <0.05). This was not attributed to steroid treatment of subjects with asthma because there was no difference in the amount of nitrite released from steroid-naive and steroid-treated cells (3.51 0.46 versus 4.27 0.7 pM nitrite, n = 10). Neither dexamethasone nor budesonide inhibited iNOS mRNA induction, protein expression, or nitrite accumulation. The cells were not steroid insensitive because steroid inhibited GM-CSF release. 

In BV-2 mouse microglial cells and rat primary microglial cell cultures exposed to lipopolysaccha-ride and interferon-y, NO was produced in a manner dependent on time and dose of activating agents (Lee et al. 2001). Inhibition of NO synthesis by iNOS inhibitor W-monomethyl-L-arginine blocked the apoptosis of activated microglial cells. 

The neuropeptide pituitary adenylate cyclaseactivating polypeptide (1 x lO" M) inhibited the reduction of PTC cell viability, NO production, expression of iNOS mRNA, and iNOS promoter activity caused by the combination of three proinflam-matory cytokines (Sekiya etal. 2000). Selective iNOS inhibitors also showed the cytoprotective effect in PTC cells. 

Whereas nitric oxide produced by constitutive eNOS is protective to the liver, NO produced by iNOS can be either toxic or protective depending on the conditions (Li and Billiar 1999). The availability of selective iNOS inhibitors and mice lacking various NOS isoforms made it possible to elucidate the precise role of NO in the liver. 

An interesting and useful example of synthesis of a-amino acids has been recently reported by Wuts and coworkers, describing a scalable process to prepare the INOS inhibitor PHA-399733 42 using the Bucherer-Bergs hydantoin synthesis as key step to introduce the amino acid function present in the final skeleton (Scheme 10.11) [41]. The methodology was applicable to the isolation of 39.9 kg (75% yield) of the racemic hydantoin 41, and the desired enantiomer was then opened in basic conditions giving the corresponding amino acid moiety. 

Wang, G.Y., Ji, B., Wang, X., and Gu, J.H. (2005). Anti-cancer effect of iNOS inhibitor and its correlation with angiogenesis in gastric cancer. World J. Gastroenterol. 11, 3830-3833. 

The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) reduce serum cholesterol levels and cardiovascular morbidity and mortality. Statins inhibit cancer cell proliferation in in vivo tumor growth in animal models (Campbell et al. 2006 Kusama et al. 2002 Paragh et al. 2003 Sivaprasad et al. 2006). Moreover, they increased iNOS mRNA and protein expression in the human breast adenocarcinoma cell line (MCF-7). NO cytotoxicity and tumor cell cytotoxicity were inhibited by iNOS inhibitors (Kotamraju et al. 2007). Based on these data, statins which are well known as a class of hyperlipidemic blockbuster drugs and are routinely used for lowering serum cholesterol levels are potential cancer drugs for use as NO inducers. 

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