Potent Intraocular Pressure Reducing Effects of AFP-168, a New Prostanoid FP Receptor Agonist

Abstract

Abstract: : Purpose: To evaluate the pharmacological characteristics of AFP-168, a newly synthesized prostaglandin (PG) F_2α derivative, prostanoid FP receptor binding affinity and intraocular pressure (IOP) lowering effect in both ocular normotensive and laser-induced ocular hypertensive monkeys were examined. Methods: For the receptor binding assay, AFP-172, PhXA85 and unoprostone, which are carboxylic acid forms of AFP-168, latanoprost and isopropyl unoprostone, respectively, were used. The binding affinity was determined by competitive binding of radiolabelled PGF_2α. For the IOP measurement study, 10 ocular normotensive and 12 laser-induced ocular hypertensive monkeys were used for single application studies, and another 10 normotensive monkeys were used for a repeated application study. Drugs (20 µl) were applied to one eye in each monkey either as a single dose or once daily for 5 days, and the contralateral eye remained untreated. The diurnal IOP change was observed using a pneumatonograph. Results: The affinity for the FP receptor of AFP-172 was 0.4 nM, which was 12 and 1700 times higher than those of PhXA85 and unoprostone, respectively. In the ocular normotensive monkey, a single application of AFP-168 (0.0005 and 0.0025%) significantly lowered IOP. The IOP reducing effect of 0.0025% AFP-168 was superior to that of 0.005% latanoprost. The once daily application of AFP-168 (0.001, 0.0025 and 0.005%) and 0.005% latanoprost for 5 days to normotensive monkeys significantly reduced diurnal IOP. All doses of AFP-168 significantly reduced IOP at the trough time point, but latanoprost did not. In the laser-induced ocular hypertensive monkey, topical application of 0.0025% AFP-168 significantly lowered IOP and the effect was greater than that of 0.005% latanoprost. Conclusions: AFP-168 has a high affinity to the prostanoid FP receptor and has potent IOP reducing effect in both ocular normotensive and laser-induced ocular hypertensive monkeys that exceeds those of latanoprost.

Keywords: eicosanoids • intraocular pressure • pharmacology