Biol. Pharm. Bull. 30(8) 1445—1449 (2007)

(IOP) is one of the risk factors for axonal damage in the optic nerve and subsequent retinal ganglion cell death, potentially leading to blindness. Currently, the use of ocular hypotensive drugs is the only available approach to glaucoma medication, and extensive efforts have been made to develop new anti-glaucoma drugs that lower IOP. In the efforts to manage and control IOP in glaucoma patients, use has been made of a number of drugs (namely, pilocarpine, b-adrenergic receptor antagonists, epinephrine and its derivatives, prostaglandin-related compounds, and carbonic anhydrase inhibitors). Such ocular hypotensive drugs operate either by altering aqueous hum or outflow by acting at sites in the trabecular meshwork (TM) or ciliary muscle, or by inhibiting the production of aqueous humor by the ciliary body. Aqueous humor outflow consists of conventional TM outflow and unconventional uveoscleral outflow. Although prostaglandin derivatives that modulate uveoscleral outflow are in use as major anti-glaucoma drugs, there are currently no drugs that act directly on TM to increase conventional outflow, even though this constitutes approximately 90% of the normal eye’s total aqueous outflow. It has been proposed that in human and primate eyes, TM plays the major role in regulating normal aqueous humor outflow-resistance so as to maintain a normal range of IOP. If this is so, an effective modulator of conventional outflow might exert a powerful ocular hypotensive effect, and thus be of great value as a next-generation anti-glaucoma drug. Ethacrynic acid (ECA), a sulfhydryl (SH)-reactive diuretic, has been observed to increase the conventional outflow facility in both enucleated calf eyes and human eyes, as well as in monkeys following anterior-chamber perfusion. Intracameral injection of up to 3 mM ECA has been found to lower IOP in monkeys, although at concentrations higher than 3 mM it produced some focal reversible corneal edema. However, a pilot study of intracameral ECA injection in humans with chronic open-angle glaucoma demonstrated remarkable degrees of both efficacy and safety. ECA thus seemed to have potential as an ocular hypotensive agent. Nevertheless, because of its possible ocular side effects, there is a need for derivatives of ECA with even greater ocular safety and corneal penetration. In fact, a number of attempts have been made to improve its profile, with respect to corneal penetration and corneal toxicity, by modifying the ECA molecule. A broader therapeutic index, which may be defined as the dose-ratio between its IOP-lowering effects and its potential side effects, would represent an advance toward the development of a drug that enhances conventional outflow. We made structural modifications to ECA involving both the phenoxyacetic acid and acryloyl moieties. This led us to a new ECA derivative, SA9000, which appeared to have a broader therapeutic index and which, upon intracameral injection at 1 mM, lowered IOP in cats and monkeys without corneal toxicity. In the present study, we evaluated SA12590 (a drug we developed from SA9000 during our attempts to improve its therapeutic index) for its effects on IOP in cats and monkeys following topical administration, its corneal toxicity in rats, and its SH reactivity in vitro.