title: 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.
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.
authors.forename: Kayla J
authors.initials: KJ
authors.lastname: Temple
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Duvernay
authors.forename: Summer E
authors.initials: SE
authors.lastname: Young
authors.affiliation: College of Science, Northwest Agriculture & Forestry University , Yangling, Shaanxi 712100, China.
authors.forename: Wandong
authors.initials: W
authors.lastname: Wen
authors.affiliation: College of Science, Northwest Agriculture & Forestry University , Yangling, Shaanxi 712100, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wu
authors.forename: Jae G
authors.initials: JG
authors.lastname: Maeng
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.affiliation: Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Hamm
authors.affiliation: Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D011743:Pyrimidines; D018179:Receptors, Thrombin; D013917:Thrombin; C112908:protease-activated receptor 4