Discovery of novel prostacyclin mimetics with highly potent and selective IP receptor agonists

Prostacyclin (PGI(2)) is primarily secreted from vascular endothelium and plays an extremely important inhibitory role in platelet aggregation and as a vasodilator in maintaining homeostatic circulation. Despite fascinating pharmacological properties, the inherent instability and side effect of prostacyclin limit its therapeutic applicability. In this paper, we described that discovery of three classes of prostacyclin mimetics without PG skeleton, which are cycloalkene skeleton type (FR 181560, FR 181157), tetrahydronaphthalene skeleton type (FK 788), and amino acid type (FR 193264, FR 193262). Several designed prostacyclin mimetics exhibited potent PGI(2) agonistic activity with good selectivity for IP receptor and bioavailability. The specific compounds were prepared by asymmetric synthesis with high selectivity. Furthermore, we also described metabolism study using rat and human liver microsomes to lead new drug design (FR 223346, FR 232149).