Effects of the New Ethacrynic Acid Derivative SA9000 on Intraocular Pressure in Cats and Monkeys

Abstract

In glaucoma, the second most common cause of blindness, an elevated intraocular pressure (IOP) is one of the risk factors for damage to the optic nerve. Currently, application of ocular hypotensive drugs is the mainstream approach to glaucoma therapy, and extensive efforts have been made to develop anti-glaucoma drugs that lower IOP. These drugs are intended either to modulate aqueous humor outflow at sites in the trabecular meshwork or ciliary muscle, [1][2][3][4][5] or to inhibit the production of aqueous humor by the ciliary body. Aqueous humor outflow consists of conventional trabecular meshwork outflow and unconventional uveoscleral outflow. It has been proposed that TM plays the major role in the regulation of normal aqueous humor outflow to maintain normal range of IOP. [6][7][8][9] At present, many ocular hypotensive agents that modulate uveoscleral outflow (such as the prostaglandin derivatives) are in use as anti-glaucoma drugs. In contrast, there are no drugs that act directly on the trabecular meshwork to increase conventional outflow, even though this constitutes approximately 90% of the normal eye's total aqueous outflow. 10)Thus, an effective modulator of conventional outflow might be capable of exerting a powerful ocular hypotensive effect and be of great value as a next-generation ocular hypotensive drug.Ethacrynic acid (ECA) is well known as a sulfhydryl (SH) reactive diuretic and a NaϪ co-transport system inhibitor, 11,12) and it has been observed to increase aqueous humor outflow and lower IOP. ECA has been reported to increase aqueous humor outflow facility in enucleated animal and human eyes and in living monkey eyes, [13][14][15][16][17] and these effects have been correlated with changes in human trabecular meshwork cell shape and cytoskeleton in vitro.18) IOP lowering also has been observed in living human eyes with glaucoma. 19) ECA thus seems to have the potential to become an ocular hypotensive agent by its targeting of the trabecular meshwork, a site at which it seems to cause reversible changes in both cell shape and attachment.18) Nevertheless, because of its possible ocular side effects, there is a need for derivatives of ECA with even greater ocular safety 16,17) and corneal penetration. 20) To broad the therapeutic index, which is shown as the ratio of doses between the IOP reducing effects and potential side effects, may lead to find the clinically useful ocular hypotensive drugs. We, therefore, synthesized thirty-two compounds and evaluated ECA derivatives that might retain the strong cytoskeletal modulating activity of ECA while having a lower cytotoxicity potential, i.e. a broader therapeutic index. The structural modifications of ECA examined involved both the phenoxyacetic acid and the acryloyl moieties. Among these, we found a new ECA derivative, SA9000, which appeared to have a broader therapeutic index. In the present study, we examined the effects of SA9000 on IOP in cats and monkeys, and also evaluated changes in corneal endothelial and epithelial morphology as surrog...

Effects of the New Ethacrynic Acid Oxime Derivative SA12590 on Intraocular Pressure in Cats and Monkeys

“…Since the latter concentration, when injected intracamerally, has an IOP-lowering effect, topical 3% SA9000 might be expected to induce an IOP-lowering effect as big as, or greater than that. 27) However, 3% SA9000 did not show significant efficacy upon topical administration, and so we hypothesized that it has a low corneal penetration rate in the current setting. An additional point is that a single drop of 3% SA9000 might be the maximum possible dosage if tolerability to corneal toxicity is to be maintained.…”

“…27) Further, topical SA9000 lowers IOP in the laser-induced ocular hypertensive monkey. 28) In addition to its greater efficacy, SA9000 has a wider safety margin than ECA (between its ocular hypotensive effect and corneal toxicity).…”

“…This led us to a new ECA derivative, SA9000, which appeared to have a broader therapeutic index 26) and which, upon intracameral injection at 1 mM, lowered IOP in cats and monkeys without corneal toxicity. 27) 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. Chemicals, Drug Preparation, and Drug Administration SA9000 (4-(2-phenyl acryloyl) cinnamic acid) and SA12590 (4-(1-methoxy imino-2-phenyl allyl) cinnamic acid) were synthesized by Santen Pharmaceutical Co., Ltd. Their structures are shown in Fig.…”

Eyedrops Containing SA9000 Prodrugs Result in Sustained Reductions in Intraocular Pressure in Rabbits

“…18 As compared to ECA, SA9000 has demonstrated superior effi cacy for the reduction of IOP in both cats and monkeys following intracameral injection with minimal ocular toxicity. 19,20 These fi ndings have suggested that SA9000 may represent a potentially useful medication for the treatment of glaucoma. Notwithstanding, several important pharmacokinetic and pharmacodynamic questions remain about the utility of SA9000 as a chronic topical treatment for glaucoma.…”

Effects of Novel Ethacrynic Acid Derivatives on Human Trabecular Meshwork Cell Shape, Actin Cytoskeletal Organization, and Transcellular Fluid Flow

“…Interestingly, in accordance with these observations, SA9000 has been shown to maximally decrease IOP with minimal side effects in living cats and monkeys, compared to ECA, as determined by intracameral injection or by topical application. 24) Therefore, SA9000 appears to be a promising novel ocular hypotensive drug worthy of further investigation per se. Modification of SA9000 should also afford enormous pharmacological potential in terms of generating derivatives that lend themselves to structure-function analysis in the context of aqueous outflow function.…”