Trans-fused 5-[(tert-Butoxtycarbonyl)amino]octahydroindenes as a protease activated receptor-1 (PAR1) antagonist

Abstract

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.

Synthesis and Crystal Structure of a New Hydrated Benzimidazolium Salt Containing Spiro Structure

“…As an important type of heterocycles, spiro compounds that contain one common atom have also shown prominent biological and pharmacological properties, such as antimicrobial [1,2], anticancer [3,4], antioxidant [5], anti-tubercular agents [6], protease activated receptor-1 (PAR1) antagonist [7], antineoplastic [8], and so on. In the last decade, the researchers' interests are now shifted to the salts of heterocyclic compounds in order to increase their solubility and efficacy.…”

Discovery of (E)‐5,5‐Difluoro‐1‐[2‐[5‐(3‐fluorophenyl)pyridin‐2‐yl]vinyl]octahydrospiro(indene‐2,5′‐oxazolidin)‐2′‐one as a PAR1 Antagonist

“…The furan‐2′‐one 11 was prepared using ketone 6 (310 mg, 1.05 mmol) as a starting material through 2‐allyl intermediate, according to the published procedures …”

“…1‐Methyl alcohols 14 – 18 were prepared starting from 1‐(benzyloxy)methyl compounds 7 – 13 independently, according to the published methods …”

“…Compounds 19–23 were prepared stating from alcohols 14 – 18 through aldehyde intermediates independently, according to the published methods …”

“…PAR1 Binding Assay. Evaluation of antagonistic effect of compounds on PAR1 was performed according to the published procedures …”