Octahydrocyclopenta[c]pyridine and octahydrocyclopenta[c]pyran analogues 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 have designed and synthesized fused 6/5 heterobicycle analogues with octahydrocyclopenta[c]pyridine or octahydrocyclopenta[c]pyran core scaffold by the insertion of heteroatom at C5 of octahydroindene ring aiming to improvement of metabolic stability. Both heterobicycle analogues showed much more improved metabolic stability compared with octahydroindenes without remarkable decrease in activity. Compounds 22 (IC50 = 110 nM) and 33 (IC50 = 50 nM) from this series showed good activity on PAR1 with moderate metabolic stability.

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

“…Using crude ketal 1 as a starting material, a compound 3 was prepared according to the published procedures (430 mg, 77% yield over two steps from compound 1 , pale yellow oil). 1 H NMR (300 MHz, CDCl 3 ) δ 1.21–2.42 (m, 12H), 6.61 (d, 1H, J = 15.9 Hz), 6.82 (dd, 1H, J = 9.0, 15.9 Hz), 7.11 (t, 1H, J = 8.7 Hz), 7.30–7.51 (m, 4H), 7.81 (d, 1H, J = 8.1 Hz), 8.75 (s, 1H); MS 387(M + ).…”

“…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 …”

“…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 …”

“…Platelet Aggregation Assay. Washed platelet aggregation and platelet rich plasma (PRP) assays were performed using whole blood and platelet concentrates purchased from Red Cross Blood Services, Daejeon, according to the published methods …”