3-Substituted thieno[2,3-b][1,4]thiazine-6-sulfonamides. A novel class of topically active carbonic anhydrase inhibitors

• Published in: Journal of medicinal chemistry Vol. 37; no. 2; pp. 240 - 247
• Main Authors: Hunt, Cecilia A, Mallorga, Pierre J, Michelson, Stuart R, Schwam, Harvey, Sondey, John M, Smith, Robert L, Sugrue, Michael F, Shepard, Kenneth L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-01-1994
• Subjects: Administration, Topical; Animals; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - pharmacology; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Humans; In Vitro Techniques; Intraocular Pressure - drug effects; Models, Molecular; Organic chemistry; Preparations and properties; Rabbits; Solubility; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Antiglaucomatous agent; Sulfur nitrogen heterocycle; Sulfonamide; Enzyme; Enzyme inhibitor; Rabbit; Lyases; Lagomorpha; In vitro; Biological activity; In vivo; Vertebrata; Mammalia; Aminolysis; Cyclization; Aminosulfone; Animal; Bicyclic compound; Carbonate dehydratase; Carbon-oxygen lyases; Hydro-lyases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00028a006

3-Aminoalkyl derivatives of thieno[2,3-b][1,4]thiazine-6-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. The compounds described were found to be excellent in vitro inhibitors of carbonic anhydrase II and in vivo to lower intraocular pressure in three rabbit models of ocular hypertension. Compounds 20A, 20B, and 20C met the requirement of formulation as a 1% solution at pH 5.2, but none of the compounds described exhibited greater activity in the normotensive albino rabbit, the alpha-chymotrypsin-treated albino rabbit, or the normotensive pigmented rabbit than MK-927 or MK-507, the present clinical candidates.