drug design structure-activity relationship (sar) prasugrel was developed with the metabolism in mind. this was done by replacing the ester group with metabolically stable ketone (group r1). also the addition of ester group at the thiophene 2-position (group r2) shifted the first step of activation from cyp2c19 to esterases and therefore is prasugrel not metabolized by cyp2c19 like clopidogrel. sar for clopidogrel and prasugrel, group r1, r2 and r3 are different. compound r1 r2 r3 clopidogrel c cl prasugrel f cangrelor and ticagrelor are new classes of reversible p2y12 receptors that have been developed to target the issues of safety (bleeding) and non-responders which the thienopyridines have. natural ligands like adenosine triphosphate (atp) were shown to inhibit platelet aggregation and has been identified as a weak antagonist. cangrelor and ticagrelor are nucleotide analogues that have a chemical structure that resembles adenosine triphosphate (atp). atp can be metabolised in cardiovascular tissues to pro-aggregatory adp, amp or adenosine. replacement of anhydride oxygen between phosphorus β (pβ) and phosphorus γ (pγ) with di-chloro or di-fluoro-methylene leads to a compound that is equipotent to atp and have a similar pka. because of this replacement the metabolism of atp to pro-aggregatory can be avoided. by adding s-propyl at the chainlength it had a major impact on the activity. addition of monosubstituted alkyl amine at the c4 position of the adenosine led to a tenfold increase in activity and also the length of the alkylamine substituent correlated with offset of effect. by adding methylsulfanylethylamino group at the c4 position and trifluoropropylsulfanyl at the chainlength leads to the formation of the drug cangrelor that has enhanced activity. cangrelor has a 78% mean recovery of adp induced platelet aggregation in rat after 20 minutes comparison to compound 1c which has a less than 10% recovery. sar for cangrelor and ticagrelor, group r1, r2 and r3 are different. compound pic50 r1 r2 r3 atp 3.6 o c c-nh2 1a 3.5 c c-nh2 1b 8.6 c-nh2 1c 9.1 cangrelor 9.4 to meet the need of the reversible orally drug ticagrelor the phosphate chain of cangrelor was replaced with an aspartic acid, resulting in 300 fold reduction in potency. the potency of ticagrelor was brought back to the same level as cangrelor by changing the purine with triazolopyrimidine. the sugar ribose unit was also replaced with a cyclopentyl group to avoid possible instability of the glycosidic bond. the group at the left hand side of the structure was replaced with the sidecain r1. the neutral sidechain r1=conh2 and r1=ch2oh were accepted with slight loss of affinity and the metabolism had shifted from biliary to hepatic metabolism. because of this, in vitro hepatic microsomal assays could be used which simplified the optimization of pharmacokinetic properties. addition of phenyl cyclopropylamine substituent in the 5 position gave high affinities. from this the first compound was found to have measurable oral bioavailability in rats (r1 =ch2oh). variation of r2 had minor impact on affinity that allowed introduction of groups to improve pharmacokinetic properties, for example r1=och2ch2oh. the introduction of fluorines at the phenyl ring and at the end of the thioether alkylchain leads to further improved metabolic stability. by replacing the fluorines at the thioether alkylchain back to s-propyl it leads to the formulation of ticagrelor. sar, group r1, r2, r3, r4 and r5 compound pic50 r1 r2 r3 r4 r5 atp 3.6 c o c-nh2 c 2a 7.0 c o 2b 9.3 n c 2c cooh=9.3 conh2 =7.7 ch2oh=7.1 cooh, conh2 or ch2oh n c 2d cooh=9.6 conh2=8.8 ch2oh=8.3 h=8.6 och2ch2oh = 8.5 cooh, conh2, ch2oh, h or och2ch2oh n c 2e 9.2 och2ch2oh n c ticagrelor 8.3 och2ch2oh n c clinical use activation of platelets and the subsequent aggregation of platelets has a crucial role maintaining normal haemostasis. disturbance in this system can lead to cerebrovascular, cardiovascular and peripheral vascular diseases where it can lead to a stroke, unstable angina and myocardial infarction. when a vessel is damaged adp is released from damaged cells and activated platelets, inducing further platelet aggregation. ticlopidine the first generation thienopyridine p2y12 receptor blocker ticlopidine was withdrawn from clinical use following high incidence of side effects such as thrombotic thrombocytopenic purpura, aplastic anaemia and neutropenia. the clinical use of the drug was quickly eclipsed by clopidogrel, since the latter had fewer gastrointestinal side effects and better hematologic safety. clopidogrel the second generation thienopyridine p2y12 receptor blocker clopidogrel is an effective antiplatelet agent useful for treatment of ischemic cerebrovascular, cardiac and peripheral arterial release. like other thienopyridine drugs, the drug was often combined with aspirin in clinical use. the clinically approved dosage of clopidogrel is a 300-mg loading dose po and a 75-mg a day maintenance dose po. for many years dual treatment with the cyclooxygenase-1 (cox-1) inhibitor aspirin and clopidogrel was routine practice and served as the main antiplatelet agents for the prevention of thrombotic events as they have the capability to powerfully manipulate platelet biology, which plays a central part in thrombosis. however, the use of these agents is still subjected to a number of important limitations such as exposure to increased risk of bleeding, making duration and dosage of clopidogrel of the utmost importance. furthermore, responsiveness to clopidogrel is not uniform and low response can lead to major adverse cardiovascular events. new generations the new generation of p2y12 blockers aimed to address these issues, promising improvement in outcome for patients. these recently developed p2y12 blockers (ticagrelor, cangrelor, prasugrel and elinogrel) provide a more consistent and stronger inhibition of platelets by more efficiently antagonizing the p2y12 receptor. however, this more potent platelet inhibition comes at the cost of a higher bleeding risk. prasugrel, a third generation thienopyridine, is metabolized more efficiently than clopidogrel and ticlopidine in the body and therefore it prevents platelet activation to a greater extent. studies have shown prasugrel to reduce the risk of stent thrombosis and myocardial infarction to much greater level than clopidogrel. the clinically approved dose of prasugrel is a 60-mg loading dose po and a 10-mg a day maintenance dose po. ticagrelor is a much more potent inhibitor of platelet aggregation than clopidogrel, however, it is associated with increase of dyspnoea episodes in patients. these episodes can range from mild to moderate severity. the approved clinical dosage of ticagrelor is a 180-mg loading dose po and a 90-mg a day maintenance dose. the only parental drug targeting the p2y12 receptor in clinical use is cangrelor. interactions the cyp2c19 enzyme metabolizes proton pump inhibitors (ppi) as well as clopidogrel. various reports have stated that there is a negative clopidogrel-omeprazole drug interaction. some studies have found that clopidogrel activity on platelets was hampered significantly by patients receiving treatment with omeprazole, a proton pump inhibitor (ppi). another study also showed lansoprazole to have hampering effects on clopidogrel activity. however, other studies have shown the intake of the ppi's pantoprazole or esomeprazole not to be associated with impaired response to clopidogrel. in 2009 the united states food and drug administration (fda) and the european medicines agency (ema) discouraged the combination of clopidogrel and ppi's, especially omeprazole, due to observations made at the time by initial cohort studies. however, newer retrospective cohort studies have not shown adverse cardiovascular events caused by clopidogrel-ppi interactions. therefore there is no definite evidence on the drug interaction effect on mortality. for patients with high risk of gastrointestinal bleeding, the risk outweighs the possible adverse cardiovascular effects. it should therefore be recommended to those patients to combine clopidogrel with less cyp2c19 inhibiting ppi's, such as pantoprazole. clopidogrel resistance the resistance of clopidogrel has emerged through the years and become a great concern for the therapy of patients with acs or undergoing pci. clopidogrel resistance is reported to vary from 4-44% between different populations and ethnic groups. patients who are exposed to clopidogrel resistance display lower activity of platelet inhibition due to decreased levels of the active metabolite of clopidogrel. this results in series of clinical incidents, e.g. ischemic and thromboembolic complications. these patients are recognized as poor- or non-responders. clopidogrel is a prodrug that needs a two-step metabolization with the help of enzymes to become an active metabolite. one of the crucial enzymes in clopidogrel metabolism is cyp2c19 which is involved in both steps of the biotransformation. a polymorphism of the enzyme cyp2c19 affects the response to clopidogrel hence decreasing enzymatic activity and therefore reducing the active metabolite of clopidogrel. the major issue of clopidogrel resistance is the interaction with other drugs, especially the proton pump inhibitor omeprazole. omeprazole and clopidogrel are metabolized by the same cyp metabolic pathway. consequently, it has been suggested that the low-responsiveness of clopidogrel, with concomitant use of omeprazole, is caused by the competition of the cyp2c19 enzyme between these two drugs. clinical approaches on how to overcome clopidogrel resistance include higher doses of clopidogrel, concomitant use with the phosphodiesterase inhibitor cilostazol or switching to a new antiplatelet agent such as prasugrel and ticagrelor. still, the major concern with these methods above are increased risk of bleeding. therefore, the need for a new antiplatelet agent with fast onset of action, less variability in response among individuals and improved safety profile is critical. future prospects the development of adp inhibitors is constantly advancing and the search for even better p2y12 antagonists is still ongoing. the cornerstone of secondary prevention of atherothrombotic events in patients with acs or undergoing pci is dual antiplatelet therapy with aspirin and clopidogrel. nevertheless, events of atherothrombosis still occur. the limitations of current antiplatelet drugs contain risk of bleeding and interindividual variability of platelet inhibitory response. the aim is to determine the optimal therapeutic window to maximize therapeutic benefits while reducing safety concerns like bleeding. consequently, the major unmet goal of adp inhibitors is to develop a potent reversible antiplatelet agent with fast onset of action, high levels of antiplatelet activity yet decreased risk of bleedings. this challenging goal together with a once-daily oral profile and optimized target selectivity would possibly be an important breakthrough in this field. vicagrel is the latest development, as of september 2017, in this sector. a novel acetate analog of clopidogrel that is expected to achieve improved antiplatelet efficiency as well as decreased risk of bleeding. preliminary pharmacokinetics studies of vicagrel has showed a higher bioavailability than in clopidogrel indicating a much lower therapeutic effective dose for vicagrel. the advantages of vicagrel over clopidogrel are considered to be no drug resistance for cyp2c19 poor metabolizers, decreased dose-related toxicity because of lower effective dose and faster onset of action.