Inhibition of prostaglandin synthesis by sodium 2-[4-(2-oxocyclopentylmethyl)phenyl] propionate dihydrate (CS-600), a new anti-inflammatory drug, and its active metabolite in vitro and in vivo.

A new anti-inflammatory agent, sodium 2-[4-(2-oxocyclopentylmethyl)phenyl]propionate dihydrate (CS-600), was investigated for its inhibition of prostaglandin (PG) synthesis in vivo and in vitro. CS-600 caused a marked decrease in the level of urinary PGE2 and PGF2 alpha in rats. The dose of CS-600 which resulted in a 50% decrease of urinary PGE2 excretion was 1.9 mg/kg, p.o., and this value agreed well with the ID50 of the drug for carrageenin edema (1.2 mg/kg, p.o.). This suggests that CS-600 inhibits prostaglandin synthesis in vivo. However, CS-600 had only weak inhibitory activity against in vitro prostaglandin synthesis by bovine seminal vesicle microsomes (IC50:760 microM). A main plasma metabolite of CS-600, which was produced by stereospecific reduction of the cyclopentanone moiety to transhydroxy cyclopentane, exhibited potent inhibitory activity toward the prostaglandin synthetase of bovine seminal vesicle microsomes (IC50:11 microM). In cell cultures of 3T6 fibroblasts from mice, CS-600 inhibited production of PGE2 and PGF2 alpha by the cells at low concentrations (IC50 for PGE2:1.6 microM). The active metabolite exhibited more potent inhibition (IC50:0.29 microM), and conversion of CS-600 into the active metabolite occurred in the cell system. Inhibition of prostaglandin synthetase in the membrane fraction of the fibroblast cells was also investigated. Available evidence indicates that CS-600 is a pro-drug and exerts its pharmacological activities after conversion to the active metabolite.