CHEMICAL AND PHARMACOLOGICAL PROPERTIES OF MK-927 - A SULFONAMIDE CARBONIC-ANHYDRASE INHIBITOR THAT LOWERS INTRAOCULAR-PRESSURE BY THE TOPICAL ROUTE

A large number of sulfonamides have now been tested by the topical route for the lowering of intraocular pressure in the normal albino rabbit. Certain compounds with favorable balance between lipid and water solubility, and high activity against carbonic anhydrase, do lower pressure as much as 3 mmHg. MK-927, a thienothiopyrane-2-sulfonamide carrying an alkylamino group of pK 5·8, has desirable physicochemical properties: good water solubility below pH 5·8, a CHCl3/buffer ratio of 0·6 at pH 5·4, and a KI value against carbonic anhydrase of 2-7 nm, depending on assay conditions. Inhibition of CO2 hydration is non-competitive. By comparison with other candidate topically active sulfonamides, it is the most effective in terms of pressure lowering times duration of action. There are no apparent systemic effects or ocular toxicity. The concentration of drug reaching the ciliary process and aqueous humor is of the same order as that following parenteral sulfonamides, so that inhibition of the enzyme exceeds 99%. MK-927 is therefore a candidate for the clinical treatment of glaucoma. © 1990.