Discovery of Potent, Selective Prostaglandin EP3/FP Dual Agonist, ONO-9054, for the Treatment of Glaucoma

Kambe Tohru, Sugimoto Isamu, Obitsu Tetsuo, Tani Kousuke, Maruyama Toru

doi:10.14894/medchem.27.2_70

<p>Glaucoma is a serious chronic ocular disease characterized by progressive optic neuropathy caused primarily by elevated intraocular pressure（IOP）, leading to visual field loss and loss of eyesight. The primary treatment for the disease aims to control intraocular pressure by topical administration of an IOP lowering agent, but current therapeutic options remain unsatisfactory. Prostaglandin EP3 receptor agonism emerged as a novel therapeutic approach, as recent publication demonstrated topically applied EP3 receptor agonists reduced IOP in animals. Based on the finding, we designed and synthesized a novel series of seven-membered ring prostacyclin analogs to identify potent and selective prostaglandin EP3/FP dual agonists by transforming the tetrahydropyran ring moiety of the hit compound. Medicinal chemistry efforts along with biological evaluation has culminated in the discovery of ONO-9054（Sepetaprost）, which produced a more profound reduction of IOP than PGF_2α analogs such as latanoprost and which demonstrated sufficient safety profiles in animals. ONO-9054 has advanced to phase 2 clinical trials in the US and Japan for the treatment of glaucoma and ocular hypertension.</p>

Discovery of Potent, Selective Prostaglandin EP3/FP Dual Agonist, ONO-9054, for the Treatment of Glaucoma

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