page_title: Adenosine diphosphate receptor inhibitor
section_title: Structure-activity relationship (SAR)
hierarchical_section_title: Adenosine diphosphate receptor inhibitor / Drug design / Structure-activity relationship (SAR)
caption_attribution_description: English: picture 31
context_page_description: Adenosine diphosphate receptor inhibitors are a drug class of antiplatelet agents, used in the treatment of acute coronary syndrome 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 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 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 and cangrelor 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.
context_section_description: 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.
  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.
  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.
caption: SAR, group R1, R2, R3, R4 and R5
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