Synthesis and biological evaluation of cyclopentyl-triazolol-pyrimidine (CPTP) based P2Y12 antagonists

Bioorg Med Chem Lett. 2014 Jan 1;24(1):141-6. doi: 10.1016/j.bmcl.2013.11.055. Epub 2013 Dec 1.

Abstract

In this Letter we describe SAR investigation on the cyclopentyl-triazolol-pyrimidine scaffold in pursuit of new oral P2Y12 inhibitors. Different synthetic routes were developed for variations at the cyclopentyl core. Optimization finally led to compound 2d which was advanced into preclinical development based on better potency and safety profile in comparison to ticagrelor.

Keywords: Anti-platelet; Excessive bleeding; P2Y(12) receptor antagonist; Ticagrelor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Cyclopentanes / administration & dosage
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology*
  • Dogs
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Platelet Aggregation / drug effects
  • Platelet-Rich Plasma / drug effects
  • Purinergic P2Y Receptor Antagonists / administration & dosage
  • Purinergic P2Y Receptor Antagonists / chemistry
  • Purinergic P2Y Receptor Antagonists / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Receptors, Purinergic P2Y12 / metabolism*
  • Structure-Activity Relationship
  • Triazoles / administration & dosage
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Cyclopentanes
  • Purinergic P2Y Receptor Antagonists
  • Pyrimidines
  • Receptors, Purinergic P2Y12
  • Triazoles
  • pyrimidine