Optimization of ketone-based P2Y(12) receptor antagonists as antithrombotic agents: pharmacodynamics and receptor kinetics considerations

  • Bioorg Med Chem Lett. 2014 Jul 1;24(13):2963-8. doi: 10.1016/j.bmcl.2014.04.001.
Fabrizio Giordanetto  1 ,  Peter Bach  2 ,  Fredrik Zetterberg  2 ,  Thomas Antonsson  2 ,  Ruth Bylund  2 ,  Johan Johansson  2 ,  Mikael Sellén  2 ,  David Brown  2 ,  Lotta Hideståhl  2 ,  Pia Berntsson  3 ,  Daniel Hovdal  4 ,  Helen Zachrisson  3 ,  Jan-Arne Björkman  3 ,  J J J van Giezen  3
Affiliations
  • 1. Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: [email protected].
  • 2. Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
  • 3. Bioscience, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
  • 4. DMPK AstraZeneca R&D, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
PMID: 24835983 DOI: 10.1016/j.bmcl.2014.04.001
Abstract

Modification of a series of P2Y12 Receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic-pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described.

Keywords
Acute coronary syndrome (ACS); Acyl sulfonamides; Esters; Ketones; P2Y(12) receptor; Piperidinyl-pyridines; Platelet aggregation; Receptor kinetics; Thromboembolism.