Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor
| Autor: | Chris Dockendorff, Lynn VerPlank, Joseph Negri, Daniel A. Smith, Robert Flaumenhaft, Stuart L. Schreiber, James R. Dilks, Louisa Dowal, Michelle Palmer, Lawrence MacPherson, Omozuanvbo Aisiku, Susanna F. Gunnink |
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| Rok vydání: | 2011 |
| Předmět: |
Agonist
Letter medicine.drug_class 1 3-diaminobenzene Allosteric regulation Peptide ML161 030204 cardiovascular system & hematology Pharmacology Biochemistry 03 medical and health sciences 0302 clinical medicine Thrombin Drug Discovery medicine platelet activation Platelet Platelet activation Receptor PAR1 inhibitor 030304 developmental biology chemistry.chemical_classification 0303 health sciences allosteric inhibitor business.industry Organic Chemistry MLPCN MLSMR 3. Good health Protease-Activated Receptor 1 chemistry cardiovascular system business medicine.drug |
| Zdroj: | ACS Medicinal Chemistry Letters |
| ISSN: | 1948-5875 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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