THE POTENTIAL THERAPEUTIC ROLE OF MONTELUKAST AND NEW HYBRID AGENTS, TXA2 ANTAGONIST-COX-2 INHIBITORS IN CARDIOVASCULAR EVENTS

The main target of my PhD research project was to explore new alternatives to reduce the cardiovascular (CV) risk targeting the arachidonic acid metabolites. Hence, I have been part of two different projects, one studying multitarget compounds with balanced COXIB and TP receptor antagonist properties, and the other evaluating the potential role of a leukotriene (LT) antagonist drug such as montelukast in improving the CV outcome. In reference to the first project, new multitarget compounds were synthesized at the University of Turin, by substituting the carboxylic function of Lumiracoxib. This strategy led to several new compounds, of which we have analyzed the platelet aggregation, total inositol phosphate production, COX-1 and COX-2 inhibitory activity. Out of all the studied compounds compound 18, the terazole derivative as well as compound 20 were the most active, with a decent balanced activity as COXIB and TP antagonist . Whereas, compound 32, displaying a functional group of terutroban did not accomplish our expectation to be a more potent TP antagonist with respect to compounds 7,18,20. Our main goal is to obtain new molecules with higher TP antagonist properties but at the same time retaining the COXIB activity. It is important to highlight that the therapeutic effect of these new compounds depend on the balance of two pharmacological profiles. The results we obtained demostrate that it is possible to have new chemical entities with higher TP antagonist potencies, and better balanced COX-2 selectivity. This approach will provide further benefits for patients with chronic pain taking a COXIB, and in patients with higher CV risk, like diabetics and hopefully can lead to a new generation of safer non steroidal antiinflammatory drugs. The second project of my PhD was focused on a LT antagonist drug such as montelukast, which is a pharmacological alternative for patients suffering asthma, allergic rhinites and urticaria. We performed a retrospective study including patients exposed or not to montelukast for a total of eight hundred asthmatic patients to assess the potential role of montelukast in primary and secondary prevention of major CV events as ischemic stroke (IS) or myocardial infarction (MI). Each of the two subjects sample was further classified in patients with or without MI or IS based on their diagnosis according to the International Classification of Diseases (ICD). The myocardial infarction event rate was almost 6 fold higher in asthmatic patients not taking montelukast and 9 fold higher for ischemic stroke events. Drug used in these patients were also monitored in order to exclude potential confounders of the results. Overall, our results suggest a reduction of CV events by montelukast, including both MI and IS eventhough the study should be expanded to a larger number of subjects. Given their association with the inflammatory onset and amplification, LTs synthesis inhibitors or LT receptor antagonists such as montelukast could be consider as potential approach for CV diseases. The results obtained during this three years of PhD cycle have shown that new innovative strategies targeting arachidonic acid metabolites can be implied to improve the CV outcome. There is still an unmet need for an anti-inflammatory treatment to reduce the CV risk, and these strategies can lead to new pharmacological approaches.