Carbonic anhydrase inhibitory activity and ocular pharmacology of organic sulfamates

Organic sulfamates are a new variation to the carbonic anhydrase (CA) inhibitor structure-action relationship. Inhibitory activity is conferred by the classic sulfonamide group, but through linkage to the benzene ring by an oxygen. AHR-16329, a representative sulfamate, has an acidic (sulfonamide, pKa 8.9) and basic (imidazole, pKa 6.0) group and has desirable physicochemical properties for topical intraocular pressure lowering: good water solubility below pH 6.0, a CHCl3/buffer ratio of 0.5 at pH 7.0 and a Kl against CA-II of 7 nM. Inhibition of CO2 hydration is noncompetitive. When applied locally to the eye, AHR-16329 reaches significant levels in ocular tissues and fluids and reduces significantly intraocular pressure. Five percent concentration gives the greatest reduction, equivalent to systemic inhibitors; 2 and 5% have similar pressure x time duration. These studies expand structure-action relations in the field of CA inhibitors and the validity of developing topical CA inhibitors for treatment of glaucoma.