Biol. Pharm. Bull. 28(12) 2189—2196 (2005)

for primary open angle glaucoma (POAG), and lowering IOP is currently the only treatment available for the management of POAG. The conventional route of aqueous humor outflow through trabecular meshwork (TM) and Schlemm’s canal (SC) is generally thought to be the major pathway for the drainage of aqueous humor from the eye. Impaired drainage through the conventional outflow pathway is believed to be responsible for the increased IOP in POAG. A balance between aqueous humor inflow by the ciliary body and its outflow through the TM determines IOP. Both TM and SC cells are thought to have important roles in the regulation of aqueous humor outflow through the conventional pathway. Since there is no single drug currently available that specifically targets the TM tissue, there is a real and urgent need for the development of novel ocular hypotensive drugs. The contractile function, cell shape, and cell adhesion properties of TM and SC cells have been implicated extensively in modulation of aqueous humor outflow through the conventional pathway, and various pharmacological agents that induce changes in cell shape, increase actin depolymerization, and decrease focal adhesions (cell–ECM interaction) have been demonstrated to consistently increase aqueous humor outflow facility in in vitro perfusion models of human and porcine enucleated eyes and in living primates. Ethacrynic acid (ECA), a sulfhydryl reactive diuretic and a Na /K /Cl co-transporter inhibitor, has been demonstrated to lower IOP in living animals, including humans, and perfusion of ECA in enucleated eyes has been reported to increase aqueous humor outflow facility through the conventional outflow pathway. In cultured TM cells, ECA induces changes in cell shape and decreases actin stress fibers and focal adhesions. Such changes are thought to influence the permeability barrier function of SC cells, the geometry of TM tissue, and ultimately, increase aqueous outflow facility. Interestingly, the non-sulfhydryl reactive phenoxyacetic acid-ticrynafen, has also been shown to increase aqueous humor outflow facility by affecting cell morphology and actin cytoskeletal organization. Although a pilot study on intracameral injection of ECA in human eyes with chronic open-angle glaucoma demonstrated both efficacy and safety, higher concentrations of the drug in nonhuman primates were found to potentially produce a reversible focal corneal edema. Therefore, there is a need for new derivatives of ECA with greater ocular safety and greater corneal penetration potential. With this goal in mind, we have produced various derivatives of ECA by structural modification of phenoxyacetic acid and acrylyol moieties. In this study we evaluated the effects of such ECA derivatives on human trabecular meshwork (HTM) cell shape, actin cytoskeletal integrity and transcellular fluid flow as morphological correlates of ocular hypotensive efficacy and therapeutic index.