Update and commentary on the pro-drug bimatoprost and a putative ‘prostamide receptor’

Abstract

The discovery of potent and efficacious intraocular pressure (IOP)-lowering FP-class prostaglandin (PG) analogs has revolutionized the treatment of ocular hypertension, a major risk factor for progression of the blinding disease glaucoma. Three isopropyl ester pro-drugs (i.e., latanoprost, travoprost and unoprostone) and one amide pro-drug (bimatoprost) of w-chain-modified analogs of PGF2α are approved for lowering IOP and treating glaucoma. It is believed that these pro-drugs are sufficiently lipophilic to readily penetrate the cornea/conjunctiva upon topical ocular dosing whereupon they are hydrolyzed with liberation of their respective free acid into the aqueous humor. The free acids of these PGs activate the FP receptors in the ciliary muscle (CM) and trabecular meshwork (TM) and cause the release of matrix metalloproteinases that digest the extracellular matrix. This remodeling within the CM and TM creates new and/or enlarges fluid flow pathways, both uveoscleral and conventional, for aqueous humor efflux, which then leads to lowering of the IOP. While it is generally believed that bimatoprost is a pro-drug and that bimatoprost free acid is the active moiety involved in lowering IOP, some have proposed that bimatoprost exerts its actions via a putative ‘prostamide receptor’. We provide an update on this topic and discuss published data that addresses the debate in this arena.