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.
Subject(s)
Analgesics/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Benzofurans/chemical synthesis , Cyclooxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors , Analgesics/chemistry , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Benzofurans/chemistry , 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 , Rats , Rats, Inbred Lew , Rats, Sprague-DawleyABSTRACT
As part of a program to establish structure-activity relationships for vanilloids, analogs of the pungent principle capsaicin, the alkyl chain portion of the parent structure (and related compounds derived from homovanillic acid) was varied. In antinociceptive and antiinflammatory assays (rat and mouse hot plate and croton oil-inflamed mouse ear), compounds with widely varying alkyl chain structures were active. Short-chain compounds were active by systemic administration in the assays mentioned above but they retained the high pungency and acute toxicity characteristic of capsaicin. In contrast, the long chain cis-unsaturates, NE-19550 (vanillyloleamide) and NE-28345 (oleylhomovanillamide), were orally active, less pungent, and less acutely toxic than capsaicin. The potential of these compounds as antiinflammatory/analgesic agents is discussed in light of recent data on the mechanism of action of vanilloids on sensory nerve fibers.
Subject(s)
Analgesics , Anti-Inflammatory Agents, Non-Steroidal , Capsaicin/analogs & derivatives , Analgesics/chemistry , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Capsaicin/chemistry , Capsaicin/toxicity , Croton Oil , Homovanillic Acid/analogs & derivatives , Homovanillic Acid/chemistry , Hot Temperature , Inflammation/chemically induced , Inflammation/drug therapy , Male , Mice , Mice, Inbred ICR , Molecular Structure , Pain Measurement , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Eight L-aspartyl dipeptides derived from heterocyclic glycine esters were prepared and evaluated as sweeteners. The fenchyl esters of L-aspartyl-2-furyl-, 2- and 3-thienyl-, and imidazolylglycine were all potently sweet with the D-2-furylglycine (+)-beta-fenchyl ester being the most potent at 16,500 times the potency of sucrose. The requirement for a planar heterocyclic group directly attached to the glycine carbon atom was demonstrated by the observation that the tetrahydrofuryl and beta-thienylalanine fenchyl esters were not sweet. The heteroaromatic glycine esters join the phenylglycine esters as a novel class of dipeptide sweeteners with very high potency.
Subject(s)
Dipeptides , Sweetening Agents/chemical synthesis , Animals , Dipeptides/chemical synthesis , Esters/chemical synthesis , Esters/pharmacology , Furans/chemical synthesis , Humans , Imidazoles/chemical synthesis , Male , Rats , Thiophenes/chemical synthesisABSTRACT
Twenty esters of L-aspartyl-D-phenylglycine, as well as two substituted analogues, an o-fluoro and a p-hydroxy-phenylglycine ester, were prepared. The L-aspartyl-D-phenylglycine (-)-alpha- and (+)-beta-fenchyl esters had the highest sweetness potency at 1200 and 3700 times that of sucrose, respectively. The high potency of these sweeteners is surprising as the phenyl group occupies a position previously believed to accommodate only much smaller groups.
