Topical carbonic anhydrase inhibitors

Abstract

Ethoxzolamide and several derivatives (1-6) were synthesized and evaluated for carbonic anhydrase inhibition (CAI), solubility, pKa, distribution, and corneal permeability. The 6-hydroxy (5) and, particularly, the 6-chloro (6) analogues have the best combination of properties for penetrating the site of action and reducing intraocular pressure. Both 5 and 6 exhibited topical effectiveness in the normal rabbit, with 6 showing greater potency.

Structure, function and applications of carbonic anhydrase isozymes

“…Ethoxzolamide also works as an inhibitor of CAs. 128 The 6-hydroxy and 6-chloro analogues have the best application in reducing intraocular pressure. Furthermore, inhibition of CAs through N-unsubstituted sulfonamide is a useful drug for ophthalmic disorders.…”

“…Furthermore, inhibition of CAs through N-unsubstituted sulfonamide is a useful drug for ophthalmic disorders. 128 Acetate, azide, cyanate, sulfide and cyanide compete with 3 Hacetazolamide for the binding site at active centre and acts as inhibitor of CAs. 129,130 Acetazolamide is CA inhibitor, used for the treatment of glaucoma, altitude sickness and benign intracranial hypertension.…”

Single and mixed poloxamine micelles as nanocarriers for solubilization and sustained release of ethoxzolamide for topical glaucoma therapy

“…ETOX structure (scheme 1a) has been used as the building block for the design of new molecules, such as dorzolamide and brinzolamide [8,9], which were approved as the first topical CAIs [3,10]. Another hydrophilic derivative, 6-hydroxyethoxzolamide, has shown efficient corneal penetration and ocular hypotensive effects in albino rabbit eyes [11].…”

Molecular Design for Enhancement of Ocular Penetration

“…61 The low solubility resulted in insufficient intraocular tissue drug concentration for the efficacy after topical instillation of aqueous suspension. To improve its poor properties, Merck Research Laboratories group has designed and synthesized many CAI inhibitor for topical instillation based on ethoxzolamide using the ring approach.…”

“…The conversion of the ethoxy group into the hydroxy group led to an increase in aqueous solubility, and this phenol L-643,799 demonstrated a weak IOP lowering effect in a rabbit model. 61 Since this conversion lowered the corneal permeability, L-643,799 was esterified to the corresponding O-pivaloyl derivative L-645,151 to increase corneal permeability like dipivefrine 62 (dipivaloyl ester prodrug of epinephrine). 63 This compound is efficacious in rabbits, but its repeated instillation for 3 months induced ocular irritation.…”