The Parmodulin NRD-21 is an Allosteric Inhibitor of PAR1 Gq Signaling with Improved Anti-Inflammatory Activity and Stability

Authors

Disha M. Gandhi, Marquette UniversityFollow
Ricardo Rosas Jr., Marquette University
Eric Greve, Marquette University
Kaitlin Kentala, Marquette University
N'Guessan D.-R, Diby, Marquette University
Vladyslava A. Snyder, Marquette University
Allison Stephans, Marquette University
Teresa H.W. Yeung, Marquette University
Saravanan Subramaniam, Blood Research Institute, Versiti, Milwaukee, WI
Elliot DiMilo, University of Wisconsin - Milwaukee
Khia E. Kurtenbach, Marquette University
Leggy A. Arnold, University of Wisconsin - Milwaukee
Hartmut Weiler, Blood Research Institute, Versiti, Milwaukee, WI
Chris Dockendorff, Marquette UniversityFollow

Document Type

Article

Language

eng

Publication Date

9-1-2019

Publisher

Elsevier

Source Publication

Bioorganic & Medicinal Chemistry

Source ISSN

0968-0896

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.

Comments

Accepted version. Bioorganic & Medicinal Chemistry, Vol. 27, No. 17 (September 1, 2019): 3788-3796. DOI. © 2019 Elsevier Ltd. Used with permission.

Recommended Citation

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.
https://epublications.marquette.edu/chem_fac/970