Physical Sciences and Mathematics Commons^™

The Parmodulin Nrd-21 Is An Allosteric Inhibitor Of Par1 Gq Signaling With Improved Anti-Inflammatory Activity And Stability, Disha M. Gandhi, Ricardo Rosas Jr., Eric Greve, Kaitlin Kentala, N'Guessan D.-R, Diby, Vladyslava A. Snyder, Allison Stephans, Teresa H.W. Yeung, Saravanan Subramaniam, Elliot Dimilo, Khia E. Kurtenbach, Leggy A. Arnold, Hartmut Weiler, Chris Dockendorff

Chemistry Faculty Research and Publications

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 …