Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor
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Dockendorff-2012-Diaminobenzenes as Selective Inhibitors.pdf
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Author(s)
Schreiber, Stuart L.
Dockendorff, Chris
Aisiku, Omozuanvbo
VerPlank, Lynn
Dilks, James R.
Smith, Daniel A.
Gunnink, Susanna F.
Dowal, Louisa
Negri, Joseph
Palmer, Michelle
Date Issued
January 2012
Journal
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society (ACS)
Citation
Dockendorff, Chris et al. “Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor.” ACS Medicinal Chemistry Letters 3.3 (2012): 232–237. © 2012 American Chemical Society
Version
Final published version
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.
MIT Department
Howard Hughes Medical Institute
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/ml2002696
