FR181157

A review.Prostacyclin (PGI₂) 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 pharmacol. 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 (FK788), and amino acid type (FR 193264, FR 193262).Several designed prostacyclin mimetics exhibited potent PGI₂ agonistic activity with good selectivity for IP receptor and bioavailability.The specific compounds were prepared by asym. 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).

A metabolism study of FR181157 (1) led to the discovery of new oxazole derivatives as active metabolites. The metabolite 6 with an epoxy ring exhibited high anti-aggregative potency with an IC(50) of 5.8 nM and potent binding affinity for the human recombinant IP receptor with a K(i) value of 6.1 nM and selectivity for human IP receptor over all other members of the human prostanoid receptor family.