Adenosine diphosphate (ADP) receptor inhibitors are a drug class of antiplatelet agents, used in the treatment of acute coronary syndrome (ACS) or in preventive treatment for patients who are in risk of thromboembolism, myocardial infarction or a stroke. These drugs antagonize the P2Y12 platelet receptors and therefore prevent the binding of ADP to the P2Y12 receptor. This leads to a decrease in aggregation of platelets, prohibiting thrombus formation. The P2Y12 receptor is a surface bound protein found on blood platelets. They belong to G protein-coupled purinergic receptors (GPCR) and are chemoreceptors for ADP.
The first drug introduced in this class was ticlopidine but due to adverse effects it is not much used today. Ticlopidine, clopidogrel and prasugrel (Efient) are all thienopyridines that cause irreversible inhibition of P2Y12 receptor. They are all prodrugs which need to be converted to an active metabolite in-vivo to inhibit the P2Y12 receptor. On the other hand, novel drugs like ticagrelor (Brilinta®) and cangrelor (Kengrexal®) are non-thienopyridines and reversibly inhibit P2Y12 meaning they act directly on the receptor without the requirement of metabolic activation and display faster onset and offset of action.
These drugs are frequently administrated in combination with aspirin (acetylsalicylic acid) to enhance platelet inhibition especially in patients with ACS or undergoing percutaneous coronary intervention (PCI).
History
Before the time of ADP inhibitors the only antiplatelet agent on the market to treat antithrombotic events was aspirin. However, because of recurrent ischemic events in high risk patients there was a basis for development of antiplatelet drugs to target other important signaling pathways.
The history of ADP inhibitors started in the year 1972 when researchers were searching for drugs similar to the anti-inflammatory agent tinoridine, a thienopyridine with anti-inflammatory and analgesic effects that had been published two years before. Based on the knowledge of thienopyridine's chemistry a significant number of derivatives of thienopyridines were synthesized. The derivatives were tested in-vivo and ex-vivo in mice and rats but the results of the tests didn't demonstrate any anti-inflammatory or analgesic effects at all but instead they displayed unexpected antiplatelet and antithrombotic effects. At that time it was very uncommon to screen for new antiplatelet agents, as the connection between platelet aggregation, thrombosis and cardiovascular incidents was disputed. However the most active derivative, ticlopidine, was selected for further development. Ticlopidine was the first-generation thienopyridine that enhanced platelet inhibition and thus used for treating in actue coronary syndrome and other cardiovascular diseases. Due to reported severe adverse effects of ticlopidine second and third-thienopyridines, clopidogrel and prasugrel, were developed.
When ticlopidine and clopidogrel were first brought to the market, ticlodipine in 1978 and clopidogrel in 1998, the mechanism of action of these two major antithrombotic drugs was not fully understood. What had been shown was that they were potent inhibitors of ADP-induced platelet aggregation, but the P2Y12 receptor had not been identified. Furthermore, it was clear that ticlopidine and clopidogrel were prodrugs which means they are inactive in-vitro and therefore need metabolism to be activated in-vivo. It wasn't until the year 2000 when the active metabolites of these drugs were isolated and characterized. About one year later the P2Y12 platelet receptor for ADP was identified. Following these discoveries the active metabolites and the enzymes responsible for their formation were progressively identified. Thus it was more than 30 years later after the discovery of ticlopidine, and more than 10 years later after the discovery of clopidogrel the mechanism of action of these two drugs was explained.
Development
Thienopyridines
Ticlopidine
The first P2Y12 inhibitors were of the thienopyridine family. They are indirect antagonists, which block the ADP-induced platelet aggregation and activation. The first drug of this class was ticlopidine and was discovered in 1972 at Porcor (now Sanofi). It was discovered while screening for a new anti-inflammatory drug based on tinoridine. It was screened with a phenotypic screening approach, tested both in vivo and ex vivo rodent models. It showed a high antiplatelet activity.
Ticlopidine had good promises and was selected for clinical trials. It was marketed in France in 1978 and went global 1991 when it reached US market for the primary and secondary prevention of stroke.