2005 - 11

Biochem Pharmacol. 2005 Nov 1;70(9):1343-51. Erratum in: Biochem Pharmacol. 2006 Feb 28;71(5):711.

A comparison of the cyclooxygenase inhibitor-NO donors (CINOD), NMI-1182 and AZD3582, using in vitro biochemical and pharmacological methods.

Young DV, Cochran ED, Dhawan V, Earl RA, Ellis JL, Garvey DS, Janero DR, Khanapure SP, Letts LG, Melim TL, Murty MG, Shumway MJ, Wey SJ, Zemtseva IS, Selig WM. Departments of Biology, 125 Spring St., Lexington, MA 02421, USA.

Cyclooxygenase (COX, EC inhibitor-nitric oxide (NO) donor (CINOD) hybrid compounds represent an attractive alternative to NSAID and coxib therapy. This report compares two CINODs, NMI-1182 (naproxen-glyceryl dinitrate) and AZD3582 (naproxen-n-butyl nitrate), for their ability to inhibit COX-1 and -2, deliver bioavailable nitric oxide, and release naproxen, using in vitro biochemical and pharmacological methods. In human whole blood, both CINODs showed inhibition, comparable to naproxen, of both COX isozymes and slowly released naproxen. Both CINODs donated bioavailable NO, as detected by cGMP induction in the pig kidney transformed cell line, LLC-PK1, but NMI-1182 was more potent by 30-100 times than AZD3582, GTN, GDN, and ISDN and considerably faster in inducing cGMP synthesis than AZD3582. The nitrate groups of GTN, NMI-1182, and AZD3582 appeared to be bioactivated via a common pathway, since each compound desensitized LLC-PK1 cells to subsequent challenge with the other compounds. Similar cGMP induction also occurred in normal, untransformed cells (human renal proximal tubule epithelial cells and hepatocytes from man, rat, and monkey); again, NMI-1182 was superior to AZD3582. NMI-1182 was also the more metabolically labile compound, releasing more absolute nitrate and nitrite (total NO(x)) in human stomach (in which NO is salutary) and liver S9 homogenates. Naproxen was also more rapidly freed from NMI-1182 than AZD3582 in human stomach, although liver S9 hydrolyzed both CINODs with similar rates. These in vitro tests revealed that NMI-1182 may be a better CINOD than AZD3582 because of its superior NO donating and naproxen liberating properties.

Expert Opin Investig Drugs. 2005 Nov;14(11):1347-58.

Nitric oxide-modulating agents for gastrointestinal disorders.

Whittle BJ. William Harvey Research Institute, Bart's and The London, Queen Mary's School of Medicine, Charterhouse Square, London, EC1M 6BQ, UK.

Almost 20 years after the identification of the biological role of nitric oxide (NO), the full therapeutic potential of novel agents that mimic the activity of NO or interfere with its synthesis has yet to be realised for utilities involving the gastrointestinal tract. New utilities for classical NO donors, which were used as vasodilators for decades, in the treatment of motility disorders have been explored and a product for treating anal fissure was recently launched. New classes of compounds incorporating a NO-donating moiety into standard non-steroidal anti-inflammatory drugs, the NO-non-steroidal anti-inflammatory drugs (NO-NSAIDs) or COX-inhibiting nitric oxide donors (CINODs) have also been developed. These have been shown to exhibit reduced gastrointestinal injury in experimental models, and reports on their efficacy and safety in Phase I and II studies are now available. Modulation of the inducible NO synthase isoform that generates excessive NO that can lead to subsequent cytotoxic moieties, such as peroxynitrite, may have therapeutic possibilities in a range of inflammatory diseases of the gut. Likewise, agents that promote the decomposition of peroxynitrite or removal of its other component, superoxide, may also prove to be of use. Further targets for pharmaceutical exploitation are likely to come from both genomic and molecular insights into the processes that regulate the NO system.