2. Academic Validation
  3. The parmodulin NRD-21 is an allosteric inhibitor of PAR1 Gq signaling with improved anti-inflammatory activity and stability

The parmodulin NRD-21 is an allosteric inhibitor of PAR1 Gq signaling with improved anti-inflammatory activity and stability

  • Bioorg Med Chem. 2019 Sep 1;27(17):3788-3796. doi: 10.1016/j.bmc.2019.06.043.
Disha M Gandhi 1,  Ricardo Rosas Jr 1,  Eric Greve 1,  Kaitlin Kentala 1,  N'Guessan D-R Diby 1,  Vladyslava A Snyder 1,  Allison Stephans 1,  Teresa H W Yeung 1,  Saravanan Subramaniam 2,  Elliot DiMilo 3,  Khia E Kurtenbach 1,  Leggy A Arnold 3,  Hartmut Weiler 4,  Chris Dockendorff 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • 2 Blood Research Institute, Versiti, Milwaukee, WI 53226, USA.
  • 3 Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, WI 53211, USA.
  • 4 Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • 5 Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA. Electronic address: [email protected].
PMID: 31320211 DOI: 10.1016/j.bmc.2019.06.043
Abstract

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.

Keywords

Allosteric inhibitor; Anti-inflammatory; Anti-platelet; Antithrombotic; Biased ligand; ML161; NRD-21; Oxazole; PAR1; Parmodulin.

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