New Ethacrynic Acid Derivatives as Potent Cytoskeletal Modulators in Trabecular Meshwork Cells

Shimazaki, Atsushi; Suhara, Hiroshi; Ichikawa, Masaki; Matsugi, Takeshi; Konomi, Koji; Takagi, Yasutaka; Hara, Hideaki; Rao, Ponugoti Vasantha; Epstein, David L.

doi:10.1248/bpb.27.846

Cited by 9 publications

(5 citation statements)

References 12 publications

(11 reference statements)

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“…28) In addition to its greater efficacy, SA9000 has a wider safety margin than ECA (between its ocular hypotensive effect and corneal toxicity). 26) However, topical administration of 3% SA9000 only tended (non-significantly) to lower IOP in our cats (Fig. 2).…”

Section: Discussionmentioning

confidence: 58%

“…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.…”

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confidence: 99%

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

Shimazaki

Kirihara

Rao

et al. 2007

Biological & Pharmaceutical Bulletin

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In glaucomatous eyes, an elevated intraocular pressure (IOP) is one of the risk factors for axonal damage in the optic nerve and subsequent retinal ganglion cell death, potentially leading to blindness. [1][2][3] 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). 4,5) 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.6-10) 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.11) 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. [12][13][14][15] 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. [16][17][18][19][20] 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. 18) However, a pilot study of intracameral ECA injection in humans with chronic open-angle glaucoma demonstrated remarkable degrees of both efficacy and safety.21) 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 19,20) and corneal penetration. 22) 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. [23][24][25] 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 2...

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Section: Discussionmentioning

confidence: 58%

mentioning

confidence: 99%

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

Shimazaki

Kirihara

Rao

et al. 2007

Biological & Pharmaceutical Bulletin

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“…The data obtained from morphological change reveals a higher efficacy and broader safety margin for SA9000, corroborating very well with our earlier independent work carried out in Santen Laboratories in Japan, in which similar results were documented using primary TM derived from bovine species. 23) Based on the ratio of cytotoxicity/loss of actin stress fibers, ECA, SA9000, and SA8248 were found to exhibit a better safety margin Ϫ9 M (1 nM) concentration, SA9995 exhibits the strongest response among the 9000 series tested in this study. Intriguingly, at 1ϫ10 Ϫ11 M, SA8248 exhibits an even stronger effect than the SA9995 compound.…”

Section: 7ϫ10mentioning

confidence: 74%

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

Rao

Shimazaki

Ichikawa

et al. 2005

Biological & Pharmaceutical Bulletin

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Increased intraocular pressure (IOP) is a major risk factor for primary open angle glaucoma (POAG), and lowering IOP is currently the only treatment available for the management of POAG. [1][2][3] 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.3) Impaired drainage through the conventional outflow pathway is believed to be responsible for the increased IOP in POAG. [2][3][4][5] A balance between aqueous humor inflow by the ciliary body and its outflow through the TM determines IOP.3) Both TM and SC cells are thought to have important roles in the regulation of aqueous humor outflow through the conventional pathway. 3,5,6) 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, [4][5][6][7][8][9] 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. [5][6][7][8][9][10][11][12][13][14] Ethacrynic acid (ECA), a sulfhydryl reactive diuretic and a NaϪ 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. 15,16) In cultured TM cells, ECA induces changes in cell shape and decreases actin stress fibers and focal adhesions. 9) Such changes are thought to influence the permeability barrier function of SC cells, the geometry of TM tissue, and ultimately, increase aqueous outflow facility. 3,8,9) 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.8) Although a pilot study on intracameral injection of ECA in human eyes with chronic open-angle glaucoma demonstrated both efficacy and safety, 17) higher concentrations of the drug in nonhuman primates were found to potentially produce a reversible focal corneal edema.18) Therefore, there is a need for new derivatives of ECA with greater ocular safety 8) and greater corneal penetration potential. 19,20) 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 correla...

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“…1), an analog of ECA, has previously been shown to display striking in vitro potency for TM cell shape alteration. 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.…”

Section: Corneal Penetration Experimentsmentioning

confidence: 99%

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

Arnold

Choksi²,

Chen³

et al. 2009

Journal of Ocular Pharmacology and Therapeutics

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Aim: Poor topical bioavailability and ocular irritation have impeded the development of the diuretic, ethacrynic acid (ECA) as a clinically useful ocular hypotensive for the treatment of glaucoma. Thus, the development of analogs and prodrugs of analogs with improved ocular penetration, potency, and tolerability is required. The aim of this work is to evaluate the corneal penetration and ocular distribution of SA9000, an ECA analog. Novel SA9000 prodrugs intended to further improve ocular pharmacodynamic effect were also evaluated. Results: SA9000 penetrated porcine corneas more effectively than ECA in corneal diffusion studies. In vivo studies in Dutch-belted (DB) rabbits indicated that topical application of a single dose (0.3%) of SA9000 could signifi cantly reduce intraocular pressure (IOP) (~25% vs. fellow untreated eye) but caused signifi cant conjunctival hyperemia. Since this hyperemia was likely the result of its inherent thiol reactivity, SA9000 was formulated with equimolar cysteine, an exogenous thiol donor. The administration of increasing SA9000-cysteine adduct concentrations (0.3%, 0.6%, 0.9%) demonstrated that they cause less ocular irritation than unadducted SA9000 but could still signifi cantly reduce IOP (0.3%: 8.7 ± 2%; 0.6%: 14.4 ± 5%; 0.9%: 23.3 ± 4.4%) versus untreated contralateral control eyes. Conclusions: These data suggest that novel thiol donor adduction can improve the ocular bioavailability and tolerability of SA9000. SA9000-cysteine prodrugs may represent a new option for the topical treatment of glaucoma.

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New Ethacrynic Acid Derivatives as Potent Cytoskeletal Modulators in Trabecular Meshwork Cells

Cited by 9 publications

References 12 publications

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

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

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

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

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