sc-57666 and Edema

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.

Topics: Animals; Anti-Inflammatory Agents; Benzofurans; Blood Platelets; Carrageenan; Cyclooxygenase Inhibitors; Edema; Humans; Lipoxygenase Inhibitors; Male; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley

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.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Benzofurans; Blood Platelets; Carrageenan; Cyclooxygenase Inhibitors; Edema; Humans; Lipoxygenase Inhibitors; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley

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.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Edema; Enzyme Inhibitors; Humans; Isoenzymes; Lipoxygenase Inhibitors; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Rats; Structure-Activity Relationship

A novel series of 5,6-diarylspiro[2.4]hept-5-enes was shown to provide highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. A study of structure-activity relationships in this series suggests that 3,4-disubstituted phenyl analogs are generally more selective than 4-substituted phenyl analogs and that replacement of the methyl sulfone group on the 6-phenyl ring with a sulfonamide moiety results in compounds with superior in vivo pharmacological properties, although with lower COX-2 selectivity. Several compounds have been shown to possess promising pharmacological properties in adjuvant-induced arthritis and edema analgesia models. The absence of gastrointestinal (GI) toxicity at 200 mpk of several selected compounds in rats and mice corresponds well with the weak potency for inhibition of COX-1 observed in the enzyme assay. Methyl sulfone 55 and sulfonamide 24 were shown to have superior in vivo pharmacological profiles, low GI toxicity, and good oral bioavailability and duration of action.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Carrageenan; Cyclooxygenase Inhibitors; Edema; Humans; Intestines; Magnetic Resonance Spectroscopy; Male; Mice; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Spiro Compounds; Stomach; Structure-Activity Relationship; Sulfonamides; Sulfones

A series of 1,2-diarylcyclopentene methyl sulfones and sulfonamides have been shown to be remarkably potent and selective cyclooxygenase-2 (COX-2) inhibitors. The methyl sulfone analogs 7 showed excellent COX-2 activity, with IC50s ranging from 0.003 (7f,n) to 0.87 (7o) microM. In addition, most analogs of 7 showed no activity (IC50 > 100 microM) against the COX-1 enzyme. Replacement of the methyl sulfone moiety with a sulfonamide group gave a slightly more potent (typically 2-5-fold) but less selective COX-2 inhibitor, mainly due to an increase (20- > 100-fold) in COX-1 activity. However, in vitro COX-1/COX-2 selectivity for the sulfonamides 8 could be increased in many cases by simply incorporating a substituent at the 3-position of the phenyl group. Furthermore, in vitro selectivity increased with the size and number of substituents, as demonstrated in the selectivity trend of 8k (8000) > 8j (1900) > 8i (500) > 8h (100). More importantly, the sulfonamide COX-2 inhibitors showed greatly enhanced oral activity in the rat model of established adjuvant-induced arthritis, with inhibition values of 79.0% (8a), 81.5% (8c), and 83.0% (8g) at 1 mg/kg. On the basis of its overall biological profile, sulfonamide 8c was evaluated as a potential clinical candidate, displaying an ED50 of 22 mpk in the rat carrageenan-induced paw edema model and an ED50 of 0.16 mpk in the rat established adjuvant-induced arthritis model with no indication of gastrointestinal toxicity in rats and mice at 200 mpk. In addition, a preparative-scale synthetic route to sulfonamide 8c has been developed.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cyclooxygenase Inhibitors; Cyclopentanes; Dose-Response Relationship, Drug; Edema; Indomethacin; Magnetic Resonance Spectroscopy; Male; Mice; Molecular Structure; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Sulfonamides; Sulfones