New Cyclooxygenase-2/5-Lipoxygenase Inhibitors. 3. 7-tert-Butyl-2,3-dihydro-3,3-dimethylbenzofuran Derivatives as Gastrointestinal Safe Antiinflammatory and Analgesic Agents:  Variations at the 5 Position

• Published in: Journal of medicinal chemistry 1998-08, Vol.41 (18), p.3515-3529
• Main Authors: Janusz, John M, Young, Patricia A, Ridgeway, James M, Scherz, Michael W, Enzweiler, Kevin, Wu, Laurence I, Gan, Lixian, Chen, Julian, Kellstein, David E, Green, Shelley A, Tulich, Jennifer L, Rosario-Jansen, Theresa, Magrisso, I. Jack, Wehmeyer, Kenneth R, Kuhlenbeck, Deborah L, Eichhold, Thomas H, Dobson, Roy L. M
• Format: Article
• Language: English
• Subjects: Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Benzofurans - chemical synthesis; Benzofurans - chemistry; Benzofurans - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carrageenan - toxicity; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Edema - chemically induced; Edema - drug therapy; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Isoenzymes - metabolism; Lipoxygenase Inhibitors; Medical sciences; Membrane Proteins; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - metabolism; Rats; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9802416

We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position:  amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.