Thieno[2,3-b]furan-2-sulfonamides as topical carbonic anhydrase inhibitors

• Published in: Journal of medicinal chemistry Vol. 35; no. 16; pp. 3027 - 3033
• Main Authors: Hartman, George D, Halczenko, Wasyl, Prugh, John D, Smith, Robert L, Sugrue, Michael F, Mallorga, Pierre, Michelson, Stuart R, Randall, William C, Schwam, Harvey, Sondey, John M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.08.1992
• Subjects: Administration, Topical; Animals; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - metabolism; Chemistry; Dansyl Compounds - metabolism; Erythrocytes - enzymology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Humans; Intraocular Pressure - drug effects; Organic chemistry; Preparations and properties; Rabbits; Solubility; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Oxygen sulfur heterocycle; Sulfonamide; Carbonic anhydrase; Ex vivo; Enzyme; Bicyclic compound; Enzyme inhibitor; Biological activity; Secondary amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00094a016

Novel 5-[(alkylamino)methyl]thieno[2,3-b]furan-2-sulfonamides were prepared and evaluated in vitro for inhibition of human carbonic anhydrase II (CA II) and ex vivo for their ability to inhibit Ca II in the albino rabbit eye after topical administration. Compound 11a was found to lower intraocular pressure (IOP) in both the alpha-CT ocular hypertensive albino rabbit and the normal albino rabbit, but was ineffective at lowering IOP in a hypertensive, pigmented monkey model. Since 11a was highly bound to ocular pigment, a series of less basic analogs was prepared. Examples in this series were both less extensively bound to ocular pigment and more active at reducing IOP in pigmented rabbits after topical dosing. Key examples displayed moderate reactivity toward glutathione.