Development of a Series of (1-Benzyl-3-(6-methoxypyrimidin-3-yl)-5-(trifluoromethoxy)-1H-indol-2-yl)methanols as Selective Protease Activated Receptor 4 (PAR4) Antagonists with in Vivo Utility and Activity Against γ-Thrombin

J Med Chem. 2016 Aug 25;59(16):7690-5. doi: 10.1021/acs.jmedchem.6b00928. Epub 2016 Aug 8.

Abstract

Here, we describe the development of a series of highly selective PAR4 antagonists with nanomolar potency and selectivity versus PAR1, derived from the indole-based 3. Of these, 9j (PAR4 IC50 = 445 nM, PAR1 response IC50 > 30 μM) and 10h (PAR4 IC50 = 179 nM, PAR1 response IC50 > 30 μM) maintained an overall favorable in vitro DMPK profile, encouraging rat/mouse in vivo pharmacokinetics (PK) and activity against γ-thrombin.

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, Thrombin / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors*
  • Thrombin / metabolism

Substances

  • Enzyme Inhibitors
  • Indoles
  • Pyrimidines
  • Receptors, Thrombin
  • Thrombin
  • protease-activated receptor 4