4-Substituted thiophene- and furan-2-sulfonamides as topical carbonic anhydrase inhibitors

• Published in: Journal of medicinal chemistry Vol. 35; no. 21; pp. 3822 - 3831
• Main Authors: Hartman, George D, Halczenko, Wasyl, Smith, Robert L, Sugrue, Michael F, Mallorga, Pierre J, Michelson, Stuart R, Randall, William C, Schwam, Harvey, Sondey, John M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-10-1992
• Subjects: Animals; carbonate dehydratase; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrase Inhibitors - therapeutic use; Carbonic Anhydrases - metabolism; Cells, Cultured; Chemistry; Disease Models, Animal; Erythrocytes - enzymology; evaluation; Exact sciences and technology; furan-2-sulfonamides; Furans - chemistry; Glutathione - metabolism; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Humans; inhibitors; Ocular Hypertension - drug therapy; Organic chemistry; Preparations and properties; Rabbits; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; synthesis; thiophene-2-sulfonamides; Thiophenes - chemistry; Thiophenes - pharmacology; Thiophenes - therapeutic use; Antiglaucomatous agent; Five membered ring; Sulfonamide; Sulfone; Enzyme; Enzyme inhibitor; Oxygen heterocycle; Ketone; In vitro; Biological activity; Sulfur heterocycle; Carbonic anhydrase; Ex vivo; Antihypertensive agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00099a010

A series of 4-substituted thiophene- and furan-2-sulfonamides was prepared and was found to possess nanomolar-level potency for inhibition of human carbonic anhydrase II in vitro. Selected examples from this group were further evaluated for their potential to act as topically effective ocular hypotensive agents in the ocular normotensive albino rabbit and the ocular alpha-chymotrypsinized rabbit. Solubility studies in water and pH 7.4 buffer were carried out to estimate the ability of compounds to be formulated in solution. The sensitization potential of key representative structures was determined by in vitro glutathione reactivity studies and guinea pig maximization testing.