Design, synthesis and biological evaluation of non-peptide PAR1 thrombin receptor antagonists based on small bifunctional templates: arginine and phenylalanine side chain groups are keys for receptor activity

摘要

In the present study, we report the synthesis and biological evaluation of a series of new non-peptide PAR1 mimetic receptor antagonists, based on conformational analysis of The S_(42)FLLR_(46) tethered ligand (TL) sequence of PAR1. These compounds incorporate the key pharmacophore groups in the TL sequence, guanidyl, amino and phenyl, which are essential for triggering receptor activity. Compounds 5 and 15 (50-100 μM) inhibited both TFLLR-amide (10 μM) and thrombin-med-iated (0.5 and 1 U/ml; 5 and 10 μM) calcium signaling in a cultured human HEK cell assay.