Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn

RCSI and UCD Researchers a Step Closer to Developing Novel Treatments for Cardiovascular Disease

18 May 2006

A recent discovery by a team of researchers from the Royal College of Surgeons in Ireland (RCSI) and University College Dublin (UCD) may lead to the development of new treatments for the prevention of thrombosis, which constitutes by far the most common form of cardiovascular disease.>Although the number of deaths from heart attack and stroke in Ireland has dropped in the past 30 years, cardiovascular disease is still one of the biggest killers in Ireland, accounting for 42 per cent of all deaths.

Pictured L to R: Dr. Marc DeVocelle and Professor Kevin Nolan, RCSI.

In cardiovascular diseases arteries can become blocked by thrombosis, which is the formation of blood clots. Non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin are used as anti-thrombotic agents in preventing heart attack and stroke.

Oxygen free radicals play a role in the induction of thrombosis. Free radicals are reactive species involved in a range of normal biological processes, such as skin ageing, and in the pathogenesis of diseases. A greater understanding of the biochemical reactions of these oxygen free radicals could lead to the development of an improved therapeutic agent for treating and preventing cardiovascular diseases.

Scientists from the Royal College of Surgeons in Ireland (RCSI), which include Centre for Synthesis and Chemical Biology (CSCB) researchers Dr. Marc Devocelle and Professor Kevin Nolan, and Professor Des Fitzgerald, Vice-President for Research at UCD, have recently synthesised some derivativesof anthranilic hydroxamic acid (AHA). These AHA compounds have the potential to be developed as therapeutic agents for inhibiting the free radical activity that can contribute to cardiovascular diseases.

NSAIDs act by interfering with the release of chemicals called prostaglandins, which are hormones produced by our bodies. The biosynthetic process of producing prostaglandins starts with the biotransformation of arachidonic acid by an enzyme called prostaglandin H2 synthase (PGHS). This enzyme is known to act at two sites - the cyclooxygenase (COX) site and the peroxidase (POX) site. Aspirin inhibits the COX site activity of this enzyme but does not act at the POX site.

Oxygen free radicals are generated at the POX site so synthesising compounds that inhibit the POX site activity of the PGHS enzyme could open up a way forward to developing anti-inflammatory agents with improved therapeutic profiles. In vitro testing of 29 AHA derivatives was carried out by Dr Anthony Chubb and Jean Lee in the RCSI and the results showed that these derivatives are true inhibitors of POX activity.

"There is no current therapeutic agent in clinical use for inhibiting POX site activity," said Dr Devocelle. "Since the COX site activity is dependent on the POX site activity, these AHA derivatives could potentially inhibit both sites and have a greater therapeutic value than NSAIDs."

About eight of the novel compounds showed significant biological activity, with one promising lead compound. The scientists then went on to synthesise and evaluate a second generation of AHA.

"Two of these new second generation compounds show superior activity compared to the best inhibitors from the original 29 compounds," concluded Professor Nolan. "We are now in the process of carrying out more in vitro testing on these second generation compounds in the hope of progressing towards clinical development."