Identification of the minimum PAR4 inhibitor pharmacophore and optimization of a series of 2-methoxy-6-arylimidazo[2, 1-b][1, 3, 4]thiadiazoles. Issue 22 (15th November 2016)

• Record Type: Journal Article
• Authors: Temple, Kayla J.; Duvernay, Matthew T.; Maeng, Jae G.; Blobaum, Anna L.; Stauffer, Shaun R.; Hamm, Heidi E.; Lindsley, Craig W.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 22(2016)
• Page Start: 5481
• Page End: 5486
• Publication Date: 2016-11-15
• Subjects: PAR4 -- Platelet aggregation -- Minimum pharmacophore -- Structure–Activity Relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.10.020
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.