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J. Biol. Chem., Vol. 268, Issue 35, 26233-26239, 12, 1993

A new class of carbonic anhydrase inhibitor

TH Maren and CW Conroy
University of Florida College of Medicine, Department of Pharmacology and Therapeutics, Gainesville 32610.

Aliphatic sulfonamides, as CH3SO2NH2, are very weak inhibitors of the carbonic anhydrases (KI congruent to 10(-4) M) and are extremely weak acids (Ka congruent to 10(-10.5) M). We now find CF3SO2NH2 a very potent inhibitor of carbonic anhydrase II (KI = 2 x 10(-9) M) and a much stronger acid (Ka = 10(-5.8) M). It freely dissolves in water, a 2% solution yielding pH 3.7, the strongest known sulfonamide acid. CHCl3/aqueous partition with this solution is very low, 0.006. The plot of CH3SO2NH2 and eight hydrophilic halo-alkyl congeners gives a linear relation over 5 orders of magnitude, pKI increasing as pKa declines. Transcorneal permeability of CF3SO2NH2 in rabbits is very high; from one drop on the cornea it rapidly gains access to the ciliary process, where it fully inhibits carbonic anhydrase and gives the maximum pressure drop (for any drug) of 6 mm Hg at 30-60 min. Action is short due to rapid disappearance of free drug from the eye at the rate of aqueous humor flow. Analyses are made of binding of CF3SO2NH2 to carbonic anhydrase and melanin in ciliary process. CF3SO2NH2 is not attacked by glutathione, is 75% bound to plasma protein, and is not taken into the renal secretory system. Excretion rate follows from glomerular filtration and tubular reabsorption. Intravenous injection thus leads to prolonged plasma levels (half-life, 24 h), a general diffusion into tissues and alkalinization of the urine, as with "classic" inhibitors. Drug is bound to carbonic anhydrase in red cells and decays with half-life of 4 days. The rapid and effective binding to carbonic anhydrase of this small hydrophilic molecule shows that complex lipophilic structures are not necessary for powerful inhibition of the enzyme. It does not appear essential for a sulfonamide to occupy a "hydrophobic pocket" in the active site cavity to react effectively at the zinc center.
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