Discovery, characterization and clinical utility of prostaglandin agonists for the treatment of glaucoma

Topical ophthalmic formulations of analogues of the endogenous arachidonic acid cyclooxygenase metabolite, PGF(2), are the standard of care treatment for the blinding disease glaucoma. These are the most potent and efficacious medical therapies for lowering intraocular pressure (IOP), the most important risk factor identified for disease progression. They have few side effects and offer the convenience of once-a-day dosing. It was initially believed that endogenous PGs raised IOP and caused substantial ocular surface adverse effects. However, carefully designed experiments demonstrated that esterification of the carboxylic acid afforded potent and efficacious topical ocular hypotensive activity. The final hurdle to be overcome was improvement of the side effect profile. A hypothesis was advanced that the IOP-lowering effect of PGF(2) isopropyl ester was due to activation of its cognate PG-FP receptor, while side effects were largely due to promiscuous interaction with other PG receptors. This hypothesis was validated by modification of the chain (carbons 13-20) to a phenyl group. This provided the first marketed FP-class PG agonist analogue (FP-PGA) ocular hypotensive agent, latanoprost. Since the introduction of latanoprost into clinical medicine to lower and control IOP, a number of additional FP-PGAs have been discovered, characterized and marketed, including travoprost, tafluprost, unoprostone isopropyl ester and bimatoprost (an amide). Linked ArticlesThis article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc