Melanin-Binding-Based\nDiscovery of Topically Instilled\nCarbonic Anhydrase Inhibitors for Targeted Delivery and Prolonged\nAction in the Eye

Glaucoma is a vision-threatening disease that is currently\ntreated\nwith intraocular-pressure-reducing eyedrops that are instilled once\nor multiple times daily. Unfortunately, the treatment is associated\nwith low patient adherence and suboptimal treatment outcomes. We developed\ncarbonic anhydrase II inhibitors (CAI-II) for a prolonged reduction\nof intraocular pressure (IOP). The long action is based on the melanin\nbinding of the drugs that prolongs ocular drug retention and response.\nOverall, 63 new CAI-II compounds were synthesized and tested for melanin\nbinding in vitro. Carbonic anhydrase affinity and IOP reduction of\nselected compounds were tested in rabbits. Prolonged reduction of\nIOP in pigmented rabbits was associated with increasing melanin binding\nof the compound. Installation of a single eye drop of a high melanin\nbinder carbonic anhydrase inhibitor (CAI) resulted in ≈2 weeks’\ndecrease of IOP, whereas the effect lasted less than 8 h in albino\nrabbits. Duration of the IOP response correlated with melanin binding\nof the compounds. Ocular pharmacokinetics of a high melanin binder\ncompound was studied after eye drop instillation to the rat eyes.\nThe CAI showed prolonged drug retention in the pigmented iris-ciliary\nbody but was rapidly eliminated from the albino rat eyes. The melanin-bound\ndrug depot maintained effective free concentrations of CAI in the\nciliary body for several days after application of a single eye drop.\nIn conclusion, melanin binding is a useful tool in the discovery of\nlong-acting ocular drugs.