新規緑内障治療薬タフルプロストの開発と工業化：ジフルオロプロスタグランジン誘導体の合成研究

概要

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Glaucoma is one of the most common, but serious eye disease that can damage the optic nerve and result in vision loss and blindness. It is thought that high pressure within the eye, known as intraocular pressure （IOP）, is the main cause of this optic nerve damage. Our research group has studied fluorinated prostaglandins （PGs） over the years, and recently discovered a 15-deoxy-15,15-difluoro-PGF2α derivative, tafluprost as a novel anti-glaucoma agent. Drug design by introducing two fluorine atoms into the PG skeleton brings various beneficial effects on chemical and metabolic stabilities and also receptor binding of the drug. A key to synthesizing the molecule is to develop an efficient geminal difluorination reaction of the enone and stereoselective Wittig reaction.Tafluprost showed an excellent pharmacological profile as an anti-glaucoma agent. It increased uveoscleral outflow of the aqueous humor, and showed a potent and stable IOP-lowering effect. In clinical studies, it also has been confirmed to have a potent IOP-lowering effect in normal tension glaucoma, a disease seen in a high ratio of the Japanese glaucoma patients. Tafluprost has been recently approved and marketed as a new anti-glaucoma agent in Japan, Europe, USA, and Asia. We herein describe our studies on the synthesis, drug design, structure-activity relationship, and molecular modeling in the development of tafluprost.