New fluoroprostaglandin F(2alpha) derivatives with prostanoid FP-receptor agonistic activity as potent ocular-hypotensive agents.

Abstract

To find new prostanoid FP-receptor agonists possessing potent ocular-hypotensive effects with minimal side effects, we evaluated the agonistic activities of newly synthesized prostaglandin F(2alpha) derivatives for the prostanoid FP-receptor both in vitro and in vivo. The iris constrictions induced by the derivatives and their effects on melanin content were examined using cat isolated iris sphincters and cultured B16 melanoma cells, respectively. The effects of derivative ester forms on miosis and intraocular pressure (IOP) were evaluated in cats and cynomolgus monkeys, respectively. Of these derivatives, 6 out of 12 compounds were more potent iris constrictors, with EC(50) values of 0.6 to 9.4 nM, than a carboxylic acid of latanoprost (EC(50)=13.6 nM). A carboxylic acid of latanoprost (100 microM) significantly increased the melanin content of cultured B16 melanoma cells, but some 15,15-difluoro derivatives, such as AFP-157 and AFP-172, did not. Topically applied AFP-168, AFP-169 and AFP-175 (isopropyl ester, methyl ester and ethyl ester forms, respectively, of AFP-172) induced miosis in cats more potently than latanoprost. AFP-168 (0.0005%) reduced IOP to the same extent as 0.005% latanoprost (for at least 8 h). These findings indicate that 15,15-difluoroprostaglandin F(2alpha) derivatives, especially AFP-168, have more potent prostanoid FP-receptor agonistic activities than latanoprost. Hence, AFP-168 may be worthy of further evaluation as an ocular-hypotensive agent.

• Authors: Tadashi Nakajima, Takeshi Matsugi, Wakana Goto, Masaaki Kageyama, Nobuaki Mori, Yasushi Matsumura, Hideaki Hara
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 26 Issue 12 Pg. 1691-5 (Dec 2003) ISSN: 0918-6158 [Print] Japan
• PMID: 14646172 (Publication Type: Comparative Study, Journal Article)

Chemical References

• (5Z)-7-((1R,2R, 3R,5S)-2-((1E)-3,3-difluoro-4-phenoxy -1-butenyl)-3,5-dihydroxycyclopentyl)-5-heptenoic acid
• 1-ethyl (5Z)-7-((1R,2R, 3R,5S)-2-((1E)-3,3-difluoro-4-phenoxy -1-butenyl)-3,5-dihydroxycyclopentyl)-5-heptenoate
• Melanins
• Prostaglandins F
• Prostaglandins F, Synthetic
• Receptors, Prostaglandin
• prostaglandin F2alpha receptor
• tafluprost
• Latanoprost
• Dinoprost

Topics

• Administration, Topical
• Animals
• Cats
• Cell Line, Tumor
• Dinoprost (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
• Drug Evaluation, Preclinical
• Forecasting
• Intraocular Pressure (drug effects, physiology)
• Iris (cytology, drug effects, physiology)
• Latanoprost
• Macaca fascicularis
• Melanins (antagonists & inhibitors, biosynthesis)
• Mice
• Miosis (chemically induced)
• Prostaglandins F (administration & dosage, pharmacokinetics, therapeutic use)
• Prostaglandins F, Synthetic (chemistry, pharmacology)
• Receptors, Prostaglandin (agonists, therapeutic use)