Scientific Publications

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

Publication TypeJournal Article
AuthorsDockendorff, C., Aisiku O., VerPlank L., Dilks JR, Smith DA, Gunnink SF, Dowal L., Negri J., Palmer M., Macpherson L., Schreiber SL, and Flaumenhaft R.
AbstractA 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.
Year of Publication2012
JournalACS medicinal chemistry letters
Volume3
Issue3
Pages232-237
Date Published (YYYY/MM/DD)2012/03/08
DOI10.1021/ml2002696
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/22408714?dopt=Abstract