title: Identification of the minimum PAR4 inhibitor pharmacophore and optimization of a series of 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazoles.
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.
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Kayla J
authors: KJ
authors: Temple
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Matthew T
authors: MT
authors: Duvernay
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Jae G
authors: JG
authors: Maeng
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Anna L
authors: AL
authors: Blobaum
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors: Shaun R
authors: SR
authors: Stauffer
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Heidi E
authors: HE
authors: Hamm
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors: Craig W
authors: CW
authors: Lindsley
mesh_terms: D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism
chemical_list: D010975:Platelet Aggregation Inhibitors; D018179:Receptors, Thrombin; D013830:Thiadiazoles; D013917:Thrombin; C112908:protease-activated receptor 4
keywords: Minimum pharmacophore; PAR4; Platelet aggregation; Structure–Activity Relationship (SAR)