title: Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354.
abstract: Herein we report the discovery and SAR of an indole-based protease activated receptor-4 (PAR-4) antagonist scaffold derived from a similarity search of the Vanderbilt HTS collection, leading to MLPCN probe ML354 (VU0099704). Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was found to have an IC50 of 140nM for PAR-4 with 71-fold selectivity versus PAR-1 (PAR-1IC50=10μM).
authors.affiliation: College of Science, Northwest Agriculture & Forestry University, Yangling, Shaanxi 712100, China; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Wandong
authors.initials: W
authors.lastname: Wen
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Summer E
authors.initials: SE
authors.lastname: Young
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Duvernay
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schulte
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Kellie D
authors.initials: KD
authors.lastname: Nance
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Melancon
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Engers
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Locuson
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: College of Science, Northwest Agriculture & Forestry University, Yangling, Shaanxi 712100, China. Electronic address: wuwenjun@nwsuaf.edu.cn.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Hamm
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA. Electronic address: shaun.stauffer@vanderbilt.edu.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D051017:Apoptosis Regulatory Proteins; D007211:Indoles; C000596297:VU0099704; C101296:prostate apoptosis response-4 protein
keywords: ML354; PAR-4 antagonist; Protease activated receptor 4