title: Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor.
abstract: A high-throughput screen of the NIH-MLSMR compound collection, along with a series of secondary assays to identify potential targets of hit compounds, previously identified a 1,3-diaminobenzene scaffold that targets protease-activated receptor 1 (PAR1). We now report additional structure-activity relationship (SAR) studies that delineate the requirements for activity at PAR1 and identify plasma-stable analogues with nanomolar inhibition of PAR1-mediated platelet activation. Compound 4 was declared as a probe (ML161) with the NIH Molecular Libraries Program. This compound inhibited platelet aggregation induced by a PAR1 peptide agonist or by thrombin but not by several other platelet agonists. Initial studies suggest that ML161 is an allosteric inhibitor of PAR1. These findings may be important for the discovery of antithrombotics with an improved safety profile.
authors.forename: Chris
authors.initials: C
authors.lastname: Dockendorff
authors.forename: Omozuanvbo
authors.initials: O
authors.lastname: Aisiku
authors.forename: Lynn
authors.initials: L
authors.lastname: Verplank
authors.forename: James R
authors.initials: JR
authors.lastname: Dilks
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Smith
authors.forename: Susanna F
authors.initials: SF
authors.lastname: Gunnink
authors.forename: Louisa
authors.initials: L
authors.lastname: Dowal
authors.forename: Joseph
authors.initials: J
authors.lastname: Negri
authors.forename: Michelle
authors.initials: M
authors.lastname: Palmer
authors.forename: Lawrence
authors.initials: L
authors.lastname: Macpherson
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: Robert
authors.initials: R
authors.lastname: Flaumenhaft