title: Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug.
abstract: To evaluate the pharmacological characteristics of AFP-168 (tafluprost), a new prostaglandin (PG) F(2alpha) derivative, we examined its receptor-binding affinities, intraocular pressure (IOP)-lowering effect, effects on aqueous humor dynamics, and stimulating effect on melanogenesis. The receptor-binding profile for AFP-172, a carboxylic acid of AFP-168, was determined by measuring muscle contractions in an organ bath, inhibition of platelet aggregation, and competitive binding of a radio-labelled ligand. For the IOP-measurement study, ocular normotensive and laser-induced ocular hypertensive cynomolgus monkeys were used, and IOP was measured using a pneumatonograph. For the studies of aqueous humor dynamics, IOP (Goldmann applanation tonometry), fluorophotometry, two-level constant pressure perfusion, and isotope dilution and accumulation techniques were used in ocular normotensive monkeys. The melanin contents in the medium and in the cell bodies of cultured B16-F0 melanoma cells were measured. The affinity for the FP receptor shown by AFP-172 (Ki : 0.4 nm) was 12 times that of PhXA85 ( Ki : 4.7 nm), a carboxylic acid of latanoprost. A single application of AFP-168 at 0.0025% significantly lowered IOP in both ocular normotensive and hypertensive monkeys (3.1 and 11.8 mmHg, respectively, p < 0.01) and latanoprost at 0.005% significantly lowered IOP (2.1 mmHg, p < 0.01 and 9.5 mmHg, p = 0.059 respectively). Once daily instillation of AFP-168 at 0.001, 0.0025, or 0.005% for 5 days in normotensive monkeys significantly reduced IOP not only for a few hours, but also at the drug-trough time 24hr after application. Latanoprost at 0.005% also reduced IOP, but not at the drug-trough time. AFP-168 decreased IOP mainly by increasing uveoscleral outflow by 65% (p < 0.05) and, as sometimes seen with other prostanoids, also increased total outflow facility (33% increase, p < 0.05). In cultured B16-F0 melanoma cells, AFP-172 (100 microM) did not stimulate melanogenesis, but PhXA85 (100 microM) did. These findings indicate that AFP-168 has a high affinity for the prostanoid FP receptor, has potent IOP-lowering effects in both ocular normotensive and hypertensive monkeys that exceed those of latanoprost, and has less stimulating effect on melanogenesis in melanoma cells.
authors.affiliation: Glaucoma Group, Research and Development Center, Santen Pharmaceutical Co., Ltd, 8916-16, Takayama-cho, Ikoma 630-0101, Nara, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Takagi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakajima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimazaki
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kageyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsugi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsumura
authors.forename: B'Ann T
authors.initials: BT
authors.lastname: Gabelt
authors.forename: Paul L
authors.initials: PL
authors.lastname: Kaufman
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001082:Aqueous Humor / Q000187:drug effects; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D005127:Eye Color / Q000187:drug effects*; D005901:Glaucoma / Q000188:drug therapy; D006168:Guinea Pigs; D007429:Intraocular Pressure / Q000187:drug effects*; D000077338:Latanoprost; D008252:Macaca fascicularis; D008297:Male; D008548:Melanosis; D011460:Prostaglandins F / Q000494:pharmacology*; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology*; D011485:Protein Binding; D011982:Receptors, Prostaglandin / Q000378:metabolism
chemical_list: C485334:(5Z)-7-((1R,2R, 3R,5S)-2-((1E)-3,3-difluoro-4-phenoxy -1-butenyl)-3,5-dihydroxycyclopentyl)-5-heptenoic acid; D000959:Antihypertensive Agents; D011460:Prostaglandins F; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; C485333:tafluprost; D000077338:Latanoprost