Bioorganic & Medicinal Chemistry
Novel analogs of the allosteric, biased PAR1 ligand ML161 (parmodulin 2, PM2) were prepared in order to identify potential anti-thrombotic and anti-inflammatory compounds of the parmodulin class with improved properties. Investigations of structure-activity relationships of the western portion of the 1,3-diaminobenzene scaffold were performed using an intracellular calcium mobilization assay with endothelial cells, and several heterocycles were identified that inhibited PAR1 at sub-micromolar concentrations. The oxazole NRD-21 was profiled in additional detail, and it was confirmed to act as a selective, reversible, negative allosteric modulator of PAR1. In addition to inhibiting human platelet aggregation, it showed superior anti-inflammatory activity to ML161 in a qPCR assay measuring the expression of tissue factor in response to the cytokine TNF-alpha in endothelial cells. Additionally, NRD-21 is much more plasma stable than ML161, and is a promising lead compound for the parmodulin class for anti-thrombotic and anti-inflammatory indications.
Gandhi, Disha M.; Rosas, Ricardo Jr.; Greve, Eric; Kentala, Kaitlin; Diby, N'Guessan D.-R,; Snyder, Vladyslava A.; Stephans, Allison; Yeung, Teresa H.W.; Subramaniam, Saravanan; DiMilo, Elliot; Kurtenbach, Khia E.; Arnold, Leggy A.; Weiler, Hartmut; and Dockendorff, Chris, "The Parmodulin NRD-21 is an Allosteric Inhibitor of PAR1 Gq Signaling with Improved Anti-Inflammatory Activity and Stability" (2019). Chemistry Faculty Research and Publications. 970.
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