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.

Available for download on Wednesday, September 01, 2021

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