Antiplatelet agents are a cornerstone in the prevention and treatment of arterial thrombosis, playing a crucial role in conditions such as myocardial infarction, stroke, and peripheral artery disease. The efficacy and characteristics of these drugs are deeply rooted in their chemical structures, which dictate their mechanisms of action, interactions with platelet targets, and pharmacokinetic profiles. For PharmD students, a solid understanding of the medicinal chemistry of antiplatelet therapy—including structure-activity relationships (SAR), prodrug activation, metabolic pathways, and the chemical basis of their therapeutic effects—is essential for optimal drug selection and patient management. This MCQ quiz will explore the key medicinal chemistry aspects of various classes of antiplatelet drugs.
1. Aspirin (acetylsalicylic acid) exerts its antiplatelet effect by irreversibly acetylating a serine residue in which enzyme?
- A. Lipoxygenase
- B. Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2)
- C. Phosphodiesterase
- D. Thromboxane synthase
Answer: B. Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2) (primarily COX-1 in platelets for antiplatelet effect at low doses)
2. Which functional group in the aspirin molecule is responsible for the acetylation of cyclooxygenase?
- A. The carboxylic acid group
- B. The acetyl group (-COCH3)
- C. The aromatic phenyl ring
- D. The hydroxyl group of salicylic acid (its metabolite)
Answer: B. The acetyl group (-COCH3)
3. Clopidogrel is a prodrug belonging to the thienopyridine class. Its activation involves:
- A. Direct binding to the P2Y12 receptor.
- B. Hydrolysis by plasma esterases as the sole step.
- C. Two-step cytochrome P450-mediated oxidation, followed by hydrolysis or further oxidation to form an active thiol metabolite.
- D. Glucuronidation in the liver.
Answer: C. Two-step cytochrome P450-mediated oxidation, followed by hydrolysis or further oxidation to form an active thiol metabolite. (Primarily CYP-mediated oxidation of the thiophene ring, then hydrolysis of an ester is one proposed pathway for some thienopyridines to eventually reveal the thiol). More accurately, it’s CYP-oxidation to 2-oxo-clopidogrel, then another CYP step to the active thiol.
Refined Answer based on typical understanding for MCQs: Answer: C. Cytochrome P450-mediated oxidation to an intermediate, followed by hydrolysis to form the active thiol metabolite.
4. The active metabolite of clopidogrel irreversibly inhibits the P2Y12 receptor by forming a __________ bond with a cysteine residue on the receptor.
- A. Hydrogen bond
- B. Ionic bond
- C. Disulfide bond (-S-S-)
- D. Van der Waals interaction
Answer: C. Disulfide bond (-S-S-)
5. Prasugrel is another thienopyridine prodrug. Compared to clopidogrel, its metabolic activation is generally considered to be:
- A. Less efficient and more dependent on CYP2C19.
- B. More efficient and less dependent on specific CYP2C19 polymorphisms, involving esterase hydrolysis followed by CYP oxidation.
- C. A single-step non-enzymatic process.
- D. Dependent on renal excretion for activation.
Answer: B. More efficient and less dependent on specific CYP2C19 polymorphisms, involving esterase hydrolysis followed by CYP oxidation.
6. Ticagrelor (a cyclopentyltriazolopyrimidine) differs from thienopyridines like clopidogrel in that ticagrelor:
- A. Is a prodrug that requires extensive hepatic metabolism.
- B. Binds irreversibly to the P2Y12 receptor.
- C. Is an orally active, direct-acting, and reversible P2Y12 receptor antagonist.
- D. Primarily inhibits COX-1.
Answer: C. Is an orally active, direct-acting, and reversible P2Y12 receptor antagonist.
7. Cangrelor is an intravenous antiplatelet agent. Its chemical structure is an analogue of:
- A. Aspirin
- B. Adenosine triphosphate (ATP), allowing reversible P2Y12 antagonism
- C. Thromboxane A2
- D. Heparin
Answer: B. Adenosine triphosphate (ATP), allowing reversible P2Y12 antagonism
8. Abciximab, a Glycoprotein IIb/IIIa inhibitor, is a:
- A. Small synthetic peptide
- B. Non-peptide small molecule
- C. Chimeric monoclonal antibody Fab fragment
- D. Cyclic heptapeptide
Answer: C. Chimeric monoclonal antibody Fab fragment
9. Eptifibatide is a Glycoprotein IIb/IIIa inhibitor whose structure is a cyclic heptapeptide containing which specific tripeptide sequence that mimics a motif in fibrinogen?
- A. RGD (Arg-Gly-Asp)
- B. KGD (Lys-Gly-Asp)
- C. PYG (Pro-Tyr-Gly)
- D. FFL (Phe-Phe-Leu)
Answer: B. KGD (Lys-Gly-Asp) (It’s an RGD mimetic, with KGD being key).
10. Tirofiban is a non-peptide, small molecule Glycoprotein IIb/IIIa inhibitor. It was designed as a mimetic of:
- A. The structure of aspirin
- B. The RGD (Arg-Gly-Asp) sequence of fibrinogen, using a tyrosine derivative scaffold
- C. The P2Y12 receptor
- D. Thromboxane A2
Answer: B. The RGD (Arg-Gly-Asp) sequence of fibrinogen, using a tyrosine derivative scaffold
11. Dipyridamole possesses a core chemical structure based on a:
- A. Quinolinone
- B. Thienopyridine
- C. Piperidino-pyrimidine derivative
- D. Steroid nucleus
Answer: C. Piperidino-pyrimidine derivative
12. Cilostazol, used for intermittent claudication, is a derivative of which heterocyclic ring system?
- A. Pyridine
- B. Quinolinone
- C. Thiazolidinedione
- D. Benzimidazole
Answer: B. Quinolinone
13. Vorapaxar is a PAR-1 antagonist. Its chemical structure is derived from:
- A. A synthetic peptide sequence
- B. Himbacine, a natural product
- C. A modified thienopyridine
- D. An ATP analogue
Answer: B. Himbacine, a natural product
14. The carboxylic acid group of aspirin (pKa ~3.5) is important for its absorption and mechanism. At gastric pH (~1-2), aspirin will be predominantly:
- A. In its ionized (anionic) form
- B. In its non-ionized (protonated) form, facilitating absorption
- C. Degraded rapidly
- D. Converted to salicylic acid
Answer: B. In its non-ionized (protonated) form, facilitating absorption
15. Hydrolysis of aspirin in the body yields salicylic acid. Salicylic acid is:
- A. A more potent irreversible inhibitor of platelet COX-1 than aspirin.
- B. An irreversible inhibitor of COX-2 only.
- C. A reversible inhibitor of COX enzymes and possesses anti-inflammatory/analgesic properties but lacks significant irreversible antiplatelet effect.
- D. Completely inactive.
Answer: C. A reversible inhibitor of COX enzymes and possesses anti-inflammatory/analgesic properties but lacks significant irreversible antiplatelet effect.
16. The thienopyridine ring system in clopidogrel and prasugrel is essential as it is the site of initial metabolic ____________ leading to activation.
- A. Hydrolysis
- B. Reduction
- C. Oxidation (by CYPs)
- D. Glucuronidation
Answer: C. Oxidation (by CYPs)
17. The active thiol metabolite of clopidogrel is unstable. Its instability contributes to its:
- A. Long duration of action.
- B. Irreversible binding to the P2Y12 receptor, as the reactive thiol readily forms a disulfide bond.
- C. High oral bioavailability.
- D. Resistance to further metabolism.
Answer: B. Irreversible binding to the P2Y12 receptor, as the reactive thiol readily forms a disulfide bond.
18. Prasugrel’s chemical structure includes an ester group that is first hydrolyzed by esterases before CYP-mediated oxidation. This initial hydrolysis step contributes to:
- A. Its decreased potency compared to clopidogrel.
- B. Its more rapid and efficient generation of the active thiol metabolite.
- C. Its classification as a direct-acting agent.
- D. Its increased susceptibility to CYP2C19 variability.
Answer: B. Its more rapid and efficient generation of the active thiol metabolite.
19. Ticagrelor’s structure, a triazolopyrimidine, allows it to bind to the P2Y12 receptor at a site distinct from ADP, acting as a(n):
- A. Irreversible covalent antagonist
- B. Non-competitive allosteric antagonist that is reversible
- C. Competitive antagonist that is also a prodrug
- D. Partial agonist
Answer: B. Non-competitive allosteric antagonist that is reversible
20. The chemical nature of abciximab as an antibody fragment means it has a ________ molecular weight and is administered ________.
- A. Low; orally
- B. High; intravenously
- C. Low; transdermally
- D. High; subcutaneously
Answer: B. High; intravenously
21. The Arg-Gly-Asp (RGD) sequence is a common motif in proteins like fibrinogen that bind to integrins. GP IIb/IIIa inhibitors like eptifibatide and tirofiban are designed to mimic this sequence to:
- A. Activate platelets.
- B. Block fibrinogen binding to the activated GP IIb/IIIa receptor.
- C. Inhibit COX-1.
- D. Activate plasminogen.
Answer: B. Block fibrinogen binding to the activated GP IIb/IIIa receptor.
22. Dipyridamole is a relatively lipophilic molecule. Its mechanism involving adenosine uptake inhibition relies on its ability to:
- A. Directly bind to adenosine receptors.
- B. Block equilibrative nucleoside transporters (ENTs).
- C. Increase adenosine synthesis.
- D. Convert adenosine to inosine.
Answer: B. Block equilibrative nucleoside transporters (ENTs).
23. The chemical structure of cilostazol contains a tetrazole ring. This moiety is often used in medicinal chemistry as a bioisostere for a:
- A. Phenyl ring
- B. Carboxylic acid group
- C. Sulfhydryl group
- D. Amine group
Answer: B. Carboxylic acid group
24. Vorapaxar’s tricyclic himbacine-derived structure allows it to act as a potent and selective antagonist of PAR-1. Its long half-life contributes to:
- A. A need for frequent daily dosing.
- B. A prolonged antiplatelet effect even after discontinuation.
- C. Rapid reversibility of its action.
- D. Minimal risk of bleeding.
Answer: B. A prolonged antiplatelet effect even after discontinuation.
25. The prodrug strategy for clopidogrel and prasugrel (esterification of a carboxylic acid) is primarily employed to:
- A. Decrease lipophilicity.
- B. Improve oral absorption and mask the reactive thiol group until systemic circulation.
- C. Increase water solubility for IV formulation.
- D. Target the drug specifically to platelets.
Answer: B. Improve oral absorption and mask the reactive thiol group until systemic circulation. (Although the thiol is formed after initial activation steps).
26. The “cyclopentyl” group in ticagrelor’s structure contributes to its:
- A. Water solubility
- B. Binding affinity and selectivity for the P2Y12 receptor
- C. Prodrug nature
- D. Irreversible binding
Answer: B. Binding affinity and selectivity for the P2Y12 receptor
27. The stability of aspirin tablets can be compromised by moisture, leading to hydrolysis into:
- A. Acetic anhydride and salicylic acid
- B. Salicylic acid and acetic acid
- C. Benzoic acid and acetic acid
- D. Phenol and carbonic acid
Answer: B. Salicylic acid and acetic acid (This is why they can smell like vinegar).
28. Which part of the cangrelor molecule (an ATP analog) is crucial for its interaction with the P2Y12 receptor, mimicking ADP/ATP?
- A. The modified sugar moiety
- B. The dichloromethylene bisphosphonate group
- C. The adenine base and the phosphate chain (or its analogue)
- D. The thio-furanose ring
Answer: C. The adenine base and the phosphate chain (or its analogue)
29. The cyclic nature of eptifibatide (a heptapeptide) is important for:
- A. Increasing its molecular weight significantly.
- B. Enhancing its oral bioavailability.
- C. Constraining its conformation to better fit the GP IIb/IIIa receptor and improve stability.
- D. Allowing it to cross the blood-brain barrier.
Answer: C. Constraining its conformation to better fit the GP IIb/IIIa receptor and improve stability.
30. The “quinolinone” scaffold in cilostazol is a key structural element. Modifications on this scaffold can affect its:
- A. COX-1 inhibitory activity
- B. Potency as a PDE3 inhibitor and pharmacokinetic properties
- C. Ability to bind to P2Y12 receptors
- D. Conversion to an active metabolite by CYP2C19
Answer: B. Potency as a PDE3 inhibitor and pharmacokinetic properties
31. The irreversible nature of aspirin’s inhibition of COX-1 means that recovery of platelet function requires:
- A. Reversal by salicylic acid.
- B. The synthesis of new platelets (thrombopoiesis).
- C. Administration of a specific antidote.
- D. Displacement of aspirin by thromboxane A2.
Answer: B. The synthesis of new platelets (thrombopoiesis).
32. The esterase-mediated hydrolysis is a key activation step for which P2Y12 inhibitor prodrug?
- A. Clopidogrel (CYP oxidation is more emphasized for initial steps)
- B. Prasugrel
- C. Ticagrelor (not a prodrug)
- D. Cangrelor (not a prodrug)
Answer: B. Prasugrel (ester hydrolysis then CYP oxidation).
33. What type of chemical interaction is primarily responsible for the binding of the active thiol metabolite of thienopyridines to the P2Y12 receptor?
- A. Ionic bonding
- B. Covalent disulfide bond formation
- C. Reversible hydrogen bonding
- D. Hydrophobic interactions only
Answer: B. Covalent disulfide bond formation
34. The “KGD” (Lys-Gly-Asp) sequence in eptifibatide is designed to mimic the fibrinogen binding site for GPIIb/IIIa. The lysine and aspartate residues provide what type of critical interactions?
- A. Primarily hydrophobic interactions
- B. Cationic (lysine) and anionic (aspartate) interactions with the receptor
- C. Covalent bond formation
- D. Metal chelation
Answer: B. Cationic (lysine) and anionic (aspartate) interactions with the receptor
35. The chemical synthesis of aspirin involves the acetylation of which precursor molecule?
- A. Acetic acid
- B. Salicylic acid
- C. Benzoic acid
- D. Phenol
Answer: B. Salicylic acid
36. The medicinal chemistry approach for developing non-peptide GP IIb/IIIa inhibitors like tirofiban involved:
- A. Modifying the structure of abciximab.
- B. Using computational modeling and SAR to design small molecules that mimic the RGD pharmacophore.
- C. Isolating them from natural sources.
- D. Random screening of existing drug libraries.
Answer: B. Using computational modeling and SAR to design small molecules that mimic the RGD pharmacophore.
37. The presence of a “leaving group” (like the acetate from the acetyl group of aspirin) is essential for which type of enzyme inhibition mechanism?
- A. Reversible competitive inhibition
- B. Irreversible covalent modification (acylation)
- C. Non-competitive allosteric inhibition
- D. Uncompetitive inhibition
Answer: B. Irreversible covalent modification (acylation)
38. The metabolism of ticagrelor involves CYP3A4 and leads to the formation of an active metabolite. This means ticagrelor itself is:
- A. An inactive prodrug.
- B. An active drug that is also metabolized to another active compound.
- C. Completely resistant to metabolism.
- D. Only metabolized by non-CYP enzymes.
Answer: B. An active drug that is also metabolized to another active compound.
39. The development of prasugrel aimed to improve upon clopidogrel by designing a prodrug that would be:
- A. Less potent to reduce bleeding.
- B. Activated more efficiently and less subject to CYP2C19 genetic variability.
- C. Reversibly acting.
- D. Administered intravenously.
Answer: B. Activated more efficiently and less subject to CYP2C19 genetic variability.
40. The basic nitrogen atoms in dipyridamole contribute to its:
- A. Ability to acetylate COX-1.
- B. Physicochemical properties, such as pKa and solubility.
- C. Prodrug nature.
- D. Irreversible binding to PDE.
Answer: B. Physicochemical properties, such as pKa and solubility.
41. Why is the carboxylic acid group important for aspirin’s activity and formulation as an acidic drug?
- A. It directly binds to the P2Y12 receptor.
- B. It allows for salt formation and influences its pKa, absorption, and distribution.
- C. It is the site of metabolic activation.
- D. It makes the drug highly lipophilic.
Answer: B. It allows for salt formation and influences its pKa, absorption, and distribution.
42. The “triazolopyrimidine” core of ticagrelor is a key structural feature. This type of heterocyclic system is known for:
- A. Being highly unstable in aqueous solutions.
- B. Its ability to participate in diverse biological interactions, often found in kinase inhibitors or receptor antagonists.
- C. Mimicking the structure of thromboxane A2.
- D. Being exclusively found in natural products.
Answer: B. Its ability to participate in diverse biological interactions, often found in kinase inhibitors or receptor antagonists.
43. The medicinal chemistry rationale behind combining aspirin with extended-release dipyridamole involves targeting:
- A. The same platelet activation pathway for synergistic effect.
- B. Two different platelet activation/aggregation pathways (TXA2 synthesis and adenosine/cAMP pathways).
- C. COX-1 and COX-2 selectively.
- D. Platelet production in the bone marrow.
Answer: B. Two different platelet activation/aggregation pathways (TXA2 synthesis and adenosine/cAMP pathways).
44. From a structural perspective, how does cangrelor achieve reversibility in P2Y12 antagonism while clopidogrel’s active metabolite is irreversible?
- A. Cangrelor forms a weaker disulfide bond.
- B. Cangrelor binds non-covalently to the P2Y12 receptor, whereas clopidogrel’s active metabolite forms a covalent disulfide bond.
- C. Cangrelor is rapidly metabolized to an inactive form.
- D. Clopidogrel is not actually irreversible.
Answer: B. Cangrelor binds non-covalently to the P2Y12 receptor, whereas clopidogrel’s active metabolite forms a covalent disulfide bond.
45. The “himicane” alkaloid scaffold of vorapaxar provides a rigid structure that presents functional groups for interaction with:
- A. The catalytic site of COX-1
- B. The ADP binding site of P2Y12 receptor
- C. The active site of thrombin
- D. The PAR-1 receptor, distinct from the thrombin catalytic site
Answer: D. The PAR-1 receptor, distinct from the thrombin catalytic site
46. The design of prasugrel includes a ketone group adjacent to the thiophene ring (after ester hydrolysis). This ketone is:
- A. The final active group binding to P2Y12.
- B. Reduced to a hydroxyl group during metabolic activation.
- C. Oxidized further by CYP enzymes as part of the activation sequence leading to the thiol.
- D. Responsible for its direct-acting nature.
Answer: C. Oxidized further by CYP enzymes as part of the activation sequence leading to the thiol. (The initial product of ester hydrolysis is a ketone, which is then oxidized by CYPs).
47. Which chemical property is critical for the IV administration of GP IIb/IIIa inhibitors like eptifibatide and tirofiban?
- A. High lipophilicity
- B. Sufficient water solubility and stability in aqueous solution
- C. Volatility
- D. Resistance to all forms of metabolism
Answer: B. Sufficient water solubility and stability in aqueous solution
48. The metabolism of the ester in clopidogrel (and other thienopyridine prodrugs) is primarily carried out by which type of enzyme before CYP action on the thiophene ring?
- A. Cytochrome P450s
- B. Carboxylesterases (leading to an inactive carboxylic acid metabolite for a large portion of the dose, not the activation pathway)
- C. Glucuronosyltransferases
- D. Sulfotransferases
Clarification: The main activation pathway involves CYPs oxidizing the thiophene. A major inactivation pathway is esterase hydrolysis of the methyl ester to an inactive acid. The question is slightly ambiguous. For activation, CYPs are key for the thiophene. For the ester itself, esterases are important, but this is mostly an inactivation route for clopidogrel. Rephrasing to target the activation thiol formation: 48. The formation of the reactive thiol group in the active metabolites of thienopyridines like clopidogrel is a result of:
- A. Direct sulfhydryl transfer from glutathione.
- B. CYP450-mediated oxidative opening of the thiophene ring.
- C. Non-enzymatic reduction.
- D. Hydrolysis of a thioester precursor.
Answer: B. CYP450-mediated oxidative opening of the thiophene ring.
49. The decision to make ticagrelor a direct-acting reversible inhibitor rather than an irreversible prodrug like clopidogrel was driven by the medicinal chemistry goal of:
- A. Increasing the risk of TTP.
- B. Achieving faster onset/offset of action and potentially more consistent platelet inhibition without reliance on metabolic activation.
- C. Making the drug less potent.
- D. Simplifying the chemical synthesis.
Answer: B. Achieving faster onset/offset of action and potentially more consistent platelet inhibition without reliance on metabolic activation.
50. What structural feature of cilostazol is common in many phosphodiesterase inhibitors and contributes to its binding in the active site of PDE3?
- A. A highly acidic carboxylic acid group
- B. A planar heterocyclic ring system (quinolinone) capable of hydrophobic and pi-stacking interactions
- C. A reactive acetyl group
- D. A sugar moiety
Answer: B. A planar heterocyclic ring system (quinolinone) capable of hydrophobic and pi-stacking interactions