Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as oral PI3Kβ inhibitors, useful as antiplatelet agents

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3936-43. doi: 10.1016/j.bmcl.2014.07.007. Epub 2014 Jul 9.

Abstract

Optimization of AZD6482 (2), the first antiplatelet PI3Kβ inhibitor evaluated in man, focused on improving the pharmacokinetic profile to a level compatible with once daily oral dosing as well as achieving adequate selectivity towards PI3Kα to minimize the risk for insulin resistance. Structure-based design and optimization of DMPK properties resulted in (R)-16, a novel, orally bioavailable PI3Kβ inhibitor with potent in vivo anti-thrombotic effect with excellent separation to bleeding risk and insulin resistance.

Keywords: Anti-thrombotic agent; Antiplatelet; Inhibitor; Insulin resistance; PI3Kβ; Phosphoinositide 3-kinase; Thromboembolism; p110β.

MeSH terms

  • Administration, Oral
  • Animals
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Male
  • Molecular Structure
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / administration & dosage
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Platelet Aggregation Inhibitors
  • Protein Kinase Inhibitors