Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354

Herein we report the discovery and SAR of an indole-based protease activated receptor-4 (PAR-4) antagonist scaffold derived from a similarity search of the Vanderbilt HTS collection, leading to MLPCN probe ML354 (VU0099704). Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was found to have an IC50 of 140 nM for PAR-4 with 71-fold selectivity versus PAR-1 (PAR-1IC50 = 10 μM).

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