Protease activated receptor 1 (PAR1) has been considered as a promising antiplatelet target to prevent thrombotic cardiovascular events in patients with prior myocardial infarction or peripheral arterial diseases. Previously, we found a series of octahydroindene analogues to have high potency on PAR1 and no significant cytotoxicity but poor metabolic stability in human and rat liver microsomes. We designed and synthesized substituted analogues of octahydroindenes at C5 or C6 aiming to improvement of metabolic stability, and identified that trans-fused 5-[(tert-butoxtycarbonyl)amino]octahydroindene analogues showed improved metabolic stability with maintaining good activity on PAR1. Especially, 2-methanesulfonate 57 (IC50 = 0.006 μM; R50 = 126.3 min in human, 83.3 min in rat), sulfamate 58 (IC50 = 0.020 μM; R50 = 52.8 min in human, 106.0 min in rat), and N-(cyclopropyl)methylsufonamide 63 (IC50 = 0.010 μM; R50 = 51.4 min in human, 90.5 min in rat) exhibited excellent activity and metabolic stability both on human and rat liver microsomes, comparable to those obtained for varapaxar (IC50 = 0.0015 μM; R50 = 83.2 min in human, 32.4 min in rat). Additionally, these compounds (57, 58, and 63) represented significant efficacy (IC50 = 0.0022, 0.0062, and 0.015 μM, each) in human washed platelet aggregation (WPA) assay without cytotoxicity and CYP3A4 inhibitory activity.