Identification of the minimum PAR4 inhibitor pharmacophore and optimization of a series of 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazoles

Bioorg Med Chem Lett. 2016 Nov 15;26(22):5481-5486. doi: 10.1016/j.bmcl.2016.10.020. Epub 2016 Oct 11.

Abstract

This letter describes the further deconstruction of the known PAR4 inhibitor chemotypes (MWs 490-525 and with high plasma protein binding) to identify a minimum PAR4 pharmacophore devoid of metabolic liabilities and improved properties. This exercise identified a greatly simplified 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazole scaffold that afforded nanomolar inhibition of both activating peptide and γ-thrombin mediated PAR4 stimulation, while reducing both molecular weight and the number of hydrogen bond donors/acceptors by ∼50%. This minimum PAR4 pharmacophore, with competitive inhibition, versus non-competitive of the larger chemotypes, allows an ideal starting point to incorporate desired functional groups to engender optimal DMPK properties towards a preclinical candidate.

Keywords: Minimum pharmacophore; PAR4; Platelet aggregation; Structure–Activity Relationship (SAR).

MeSH terms

  • Blood Platelets / cytology
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Humans
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology
  • Receptors, Thrombin / antagonists & inhibitors*
  • Receptors, Thrombin / metabolism
  • Thiadiazoles / chemistry*
  • Thiadiazoles / pharmacology*
  • Thrombin / metabolism

Substances

  • Platelet Aggregation Inhibitors
  • Receptors, Thrombin
  • Thiadiazoles
  • Thrombin
  • protease-activated receptor 4