Design and Evaluation of Heterobivalent PAR1–PAR2 Ligands as Antagonists of Calcium Mobilization

04 June 2018, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

A novel class of bivalent ligands targeting putative Protease-Activated Receptor (PAR) heteromers has been prepared based upon reported antagonists for the subtypes PAR1 and PAR2. Modified versions of the PAR1 antagonist RWJ-58259 containing alkyne adapters were connected via cycloaddition reactions to azide-capped polyethylene glycol (PEG) spacers attached to imidazopyridazine-based PAR2 antagonists. Initial studies of the PAR1–PAR2 antagonists indicated that they inhibited G alpha q-mediated calcium mobilization in endothelial and cancer cells driven by both PAR1 and PAR2 agonists. Compounds of this novel class hold promise for the prevention of restenosis, cancer cell metastasis, and other proliferative disorders.

Keywords

bivalent ligand
protease-activated receptors
PAR1 antagonist
PAR2 antagonist
calcium mobilization
restenosis inhibitor
metastasis inhibitor

Supplementary materials

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Title
2018 05 21 PAR1 antag-PAR2-antag ChemRxiv SI
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