An attempt to develop a water-soluble carbonic anhydrase inhibitor focused on exploring structure-activity relationships in the thienothiopyransulfonamide class. The strategy to influence water solubility while retaining carbonic anhydrase activity involved the introduction of a hydroxyl moiety and adjusting the oxidation state of the sulfur on the thiopyran portion of the molecule. Compounds 4 and 17 best fit the criteria of aqueous solubility and inhibitory potency vs. human carbonic anhydrase II and are candidates for evaluation as topically effective antiglaucoma agents.

Derivatives of benzo[b]thiophene-2-sulfonamide were prepared to investigate their potential utility as topically active inhibitors of ocular carbonic anhydrase. Such an agent would be useful in the treatment of glaucoma. Among the compounds described are 6-hydroxybenzo[b]thiophene-2-sulfonamide (16) and its acetate ester (23), which are among the most potent ocular hypotensive agents in this class, as assessed in the alpha-chymotrypsinized rabbit. These compounds were selected for clinical evaluation.

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A series of trichloroacetamidine derivatives, obtained by addition of amines to trichloroacetonitrile, was evaluated for positive inotropic activity on isolated cat heart papillary muscles. Increased contractility, not antagonized by beta-adrenergic blockade with sotalol or reserpine pretreatment, was observed in this assay with a variety of N-substituted trichloroacetamidine derivatives. More extensive pharmacological studies with the 3-indolylmethyl analogue 2 showed that this amidine in dogs, 5 mg/kg iv, produced a positive inotropic effect more pronounced than that of ouabain, 50 microgram/kg iv. Several of the trichloroacetamidines were found to be inhibitors of guinea pig kidney and calf heart Na-K-dependent ATPase and to have specificity for these enzymes different from that of ouabain. Bacterial mutagenic activity was observed with three members, 2,3, and 12, of the series.

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