ABSTRACT
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.
Subject(s)
Analgesics , Anti-Inflammatory Agents, Non-Steroidal , Benzofurans , Cyclooxygenase Inhibitors , Enzyme Inhibitors , Isoenzymes/metabolism , Lipoxygenase Inhibitors , Prostaglandin-Endoperoxide Synthases/metabolism , 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 , 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 , Membrane Proteins , Rats , Structure-Activity RelationshipABSTRACT
A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were prepared and evaluated as potential nonsteroidal antiinflammatory and analgesic agents. Interest in this class of compounds arose when a DHDMBF was found to be an active metabolite of the di-tert-butylphenol antiinflammatory agent tebufelone. We have now found that a variety of 5-keto-substituted DHDMBFs have good in vivo antiinflammatory and analgesic activity after oral administration. These compounds inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) in vitro. The cyclooxygenase inhibition was found to be selective for the cyclooxygenase-2 isoform, and this combination of COX-2/5-LOX inhibition may be responsible for the gastrointestinal safety of compounds such as 30.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Benzofurans/chemical synthesis , Cyclooxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Benzofurans/pharmacology , Blood Platelets/drug effects , Blood Platelets/enzymology , Carrageenan/adverse effects , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacology , Edema/chemically induced , Edema/drug therapy , Humans , Male , Rats , Rats, Inbred Lew , Rats, Sprague-DawleyABSTRACT
A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were found to be nonsteroidal antiinflammatory and analgesic agents. These compounds are inhibitors of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX) with selectivity for the COX-2 isoform. A series of analogues were prepared to investigate the scope of this lead. Five ketone side chains from active DHDMBFs were used to investigate the effects of changes in the DHDMBF "core": the size and identity of the heterocycle and the substituent requirements of the heterocycle and phenyl ring. Biological testing showed that a variety of structural changes can be accommodated, but no structure was clearly superior to the DHDMBF structure.
