The replacement of a problematic indazole core present in a known class of PAR4 antagonists was successfully implemented through the introduction of an indole core structure. Subsequent libraries of compounds exploring the structure activity relationship (SAR) for this indole series provided PAR4 antagonists with potencies only in the micro-molar range. As a result, a similarity search was conducted which identified 160 candidates from our in-house sample collection for testing against PAR4. From this redirected effort arose ML354, a selective PAR4 antagonist with good potency (PAR4 IC50 = 140 nM), and reasonable selectivity versus PAR1. A lead profiling screen (Pan Labs) identified only 3 potential off-target binding activities, which were all quite weak and unrelated to relevant PAR4 biology. This compound/series also displays improved physical properties and is very amenable to future medicinal chemistry development. Although this molecule contains a nitro group, it still represents the best-in-class PAR4 antagonist for use in vitro, and holds great promise for the development of future in vivo tools.