Designing Natural Product Hybrids Bearing Triple Antiplatelet Profile and Evaluating Their Human Plasma Stability

Methods Mol Biol. 2018:1824:371-385. doi: 10.1007/978-1-4939-8630-9_22.

Abstract

Cardiovascular diseases (CVDs) are becoming major contributors to the burden of disease due to genetic and environmental factors. Despite current standard oral care, cardiovascular risk remains relatively high. A triple antiplatelet therapy with a cyclooxygenase-1 (COX-1) inhibitor, a P2Y12 receptor antagonist, and a protease-activated receptor-1 (PAR-1) antagonist has been established in the secondary prevention of atherothrombosis in patients with acute myocardial infraction and in those with peripheral artery disease. However, due to the combinatorial use of three different drugs, patients receiving this triple therapy are exposed to enhanced risk of bleeding. Conforming to polypharmacology principles, the discovery of a single compound that can simultaneously block the three platelet activation pathways (PAR-1, P2Y12, and COX-1) is of importance. Natural products have served as an inexhaustible source of bioactive compounds presenting a diverse pharmaceutical profile, including anti-inflammatory, antioxidant, anticancer, and antithrombotic activity. Indeed, principal component analysis indicated that natural products have the potential to inhibit the three aforementioned pathways, though existed reports refer to single inhibition mechanism on specific receptor(s) implicated in platelet activation. We thus set out to explore possibilities that take advantage of this potential of natural products and shape the basis to produce novel compounds that could simultaneously target PAR-1, P2Y12, and COX-1 platelet activation pathways. Polyunsaturated fatty acids (PUFAs) have multiple effects leading to improvements in blood pressure and cardiac function and arterial compliance. A promising approach to achieve the desirable goal is the bioconjugation of natural products with PUFAs. Herein, we describe the principles that should be followed to develop molecular hybrids bearing triple antiplatelet activity profile.

Keywords: Flavonoids; LC-MS; Liquid chromatography; Plasma stability; Polyunsaturated fatty acids; Triple antiplatelet activity.

MeSH terms

  • Blood Platelets* / chemistry
  • Blood Platelets* / metabolism
  • Cyclooxygenase 1*
  • Cyclooxygenase Inhibitors* / chemistry
  • Cyclooxygenase Inhibitors* / pharmacokinetics
  • Cyclooxygenase Inhibitors* / pharmacology
  • Drug Evaluation, Preclinical / methods
  • Drug Stability
  • Fatty Acids, Unsaturated* / chemistry
  • Fatty Acids, Unsaturated* / pharmacokinetics
  • Fatty Acids, Unsaturated* / pharmacology
  • Humans
  • Plasma / chemistry*
  • Platelet Aggregation Inhibitors* / chemistry
  • Platelet Aggregation Inhibitors* / pharmacokinetics
  • Platelet Aggregation Inhibitors* / pharmacology
  • Purinergic P2Y Receptor Antagonists / chemistry
  • Purinergic P2Y Receptor Antagonists / pharmacokinetics
  • Purinergic P2Y Receptor Antagonists / pharmacology
  • Receptor, PAR-1 / antagonists & inhibitors*
  • Receptor, PAR-1 / metabolism
  • Receptors, Purinergic P2Y12*

Substances

  • Cyclooxygenase Inhibitors
  • Fatty Acids, Unsaturated
  • P2RY12 protein, human
  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Receptor, PAR-1
  • Receptors, Purinergic P2Y12
  • Cyclooxygenase 1
  • PTGS1 protein, human