Target Analysis - Purinoreceptors
P2Y12 and the anti-platelet drugs
Among the first P2 purinoreceptor-targeted compounds synthesized were the antiplatelet drug ticlopidine and its analogue, clopidogrel. The role of ADP in the function of platelets has long been known. Following activation, platelets secrete a number of agonists including ADP and TXA2, which activate a pathway for platelet aggregation and clot formation. There are a number of diseases and medical procedures that leave patients prone to development of life-threatening clots, for which blocking the action of ADP via P2Y12 receptors has proved immensely important.
Clopidogrel (marketed as Plavix and Isover by Sanofi-Aventis and Bristol-Myers Squibb, respectively) is a potent P2Y12 receptor antagonist indicated for the prevention of ischaemic events in patients with atherosclerosis, the treatment of acute coronary syndrome (ACS) and the prevention of thrombosis following the placement of coronary stents. In 2007, Clopidogrel ranked as the second-highest selling drug in the world, with sales of US$7.3 billion.
There are four novel P2Y12 receptor antagonists in clinical development, which could potentially compete for this lucrative market as they boast a number of benefits over clopidogrel. The most advanced of these drugs is Daiichi Sankyo's prasurgrel, which has been submitted for approval in the EU and the US. In a Phase III superiority trial against clopidogrel in ACS patients, prasugrel significantly reduced the risk of cardiovascular death, non-fatal heart attack and non-fatal stroke by 19%. A staggering 40% reduction in risk of heart attack was observed in a subgroup analysis of patients with diabetes. Another promising compound is Portola's PRT- 060128 (elinogrel); it is the only reversible inhibitor of P2Y12 in clinical development, which may reduce the incidence of bleeding compared with the likes of clopidogrel and prasugrel. It also has the benefit of an instant onset of action, as it has no prodrug properties. Both iv and oral formulations are under development for acute (hospital) and chronic settings. It is currently in a Phase II trial comparing it to clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI), to assess if these favourable chemical properties translate into a safer and more efficacious drug.
