New Fluoroprostaglandin F_<2α> Derivatives with Prostanoid FP-Receptor Agonistic Activity as Potent Ocular-Hypotensive Agents (Pharmacology)

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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_<2α> 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 9.4nM, than a carboxylic acid of latanoprost (EC_<50>=13.6nM). A carboxylic acid of latanoprost (100μM) 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 8h). These findings indicate that 15,15-difluoroprostaglandin F_<2α> 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.
公益社団法人日本薬学会の論文
2003-12-01

New Fluoroprostaglandin F_<2α> Derivatives with Prostanoid FP-Receptor Agonistic Activity as Potent Ocular-Hypotensive Agents (Pharmacology)

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