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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.

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The 3-dimensional structure of human carbonic anhydrase I1 (HCAII; EC 4.2.1.1) complexed with 3 structurally related inhibitors, l a , l b , and I C , has been determined by X-ray crystallographic methods. The 3 inhibitors ( l a = C8H,2N204S3) vary only in the length of the substituent on the 4-amino group: l a , proton; Ib, methyl; and IC, ethyl. The binding constants (Ki's) for la, Ib, and I C to HCAII are 1.52, 1.88, and 0.37 nM, respectively. These structures were solved to learn if any structural cause could be found for the difference in binding. In the complex with inhibitors l a and l b , electron density can be observed for His-64 and a bound water molecule in the native positions. When inhibitor IC is bound, the side chain attached to the 4-amino group is positioned so that His-64 can only occupy the alternate position and the bound water is absent. While a variety of factors contribute to the observed binding constants, the major reason IC binds tighter to HCAII than does l a or l b appears to be entropy: the increase in entropy when the bound water molecule is released contributes to the increase in binding and overcomes the small penalty for putting the His-64 side chain in a higher energy state.

The synthesis of a series of isoelectronic analogues of (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1) are described; included in this group are examples of thiazole, isothiazole, thiadiazole, pyrazine, and the structurally related naphthyridines. All of the compounds are similar to 1 in that they contain a cyano group ortho to the aminohydroxypropoxy side chain and meta to the nitrogen heteroatom. In addition, several related examples, having additional nuclear substituents and/or groups other than CN in the position adjacent to the aminohydroxypropoxy group, were prepared, and beta-adrenoceptor antagonist activity and vasodilating potency were determined. Three compounds, thiazole 2 and isothiazoles 3 and 27, effectively lowered mean arterial pressure in the SH rat at 5 mg/kg. Compounds 2, 3, and 27 increased iliac blood flow and exhibited beta-adrenergic blocking properties in the dog.