Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor

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Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor

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Title: Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor
Author: Dockendorff, Chris; VerPlank, Lynn; Dilks, James R.; Gunnink, Susanna F.; Palmer, Michelle; MacPherson, Lawrence; Aisiku, Omozuanvbo Reginald; Smith, Daniel A.; Dowal, Louisa; Schreiber, Stuart L.; Flaumenhaft, Robert C.; Negri, Joseph Michael

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Citation: Dockendorff, Chris, Omozuanvbo Aisiku, Lynn VerPlank, James R. Dilks, Daniel A. Smith, Susanna F. Gunnink, Louisa Dowal, et al. 2012. Discovery of 1,3-diaminobenzenes as selective inhibitors of platelet activation at the PAR1 receptor. ACS Medicinal Chemistry Letters 3(3): 232-237.
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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.
Published Version: doi:10.1021/ml2002696
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297361/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10304424
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