Subject(s)
Cyclooxygenase Inhibitors/pharmacology , Isoenzymes/antagonists & inhibitors , Isoenzymes/pharmacology , Isoxazoles/pharmacology , Prostaglandin-Endoperoxide Synthases/pharmacology , Acylation , Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/administration & dosage , Dogs , Injections , Isoxazoles/administration & dosage , Macaca fascicularis , Male , RatsSubject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Isoenzymes/pharmacology , Isoxazoles/chemical synthesis , Prostaglandin-Endoperoxide Synthases/pharmacology , Sulfonamides/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Cyclooxygenase 2 , Edema/drug therapy , Enzyme Inhibitors/pharmacology , Humans , Isoenzymes/blood , Isoxazoles/pharmacology , Membrane Proteins , Prostaglandin-Endoperoxide Synthases/blood , Rats , Recombinant Proteins/antagonists & inhibitors , Sulfonamides/pharmacologyABSTRACT
A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition.
Subject(s)
Isoenzymes/drug effects , Prostaglandin-Endoperoxide Synthases/drug effects , Sulfones/chemistry , Thiazoles/chemical synthesis , Animals , Cyclooxygenase 2 , Inhibitory Concentration 50 , RatsABSTRACT
A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo.
Subject(s)
Isoenzymes/drug effects , Prostaglandin-Endoperoxide Synthases/drug effects , Sulfonamides/chemistry , Thiazoles/chemical synthesis , Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/chemical synthesis , Humans , Membrane Proteins , Models, Chemical , RatsABSTRACT
A series of methysulfonyl or sulfonamido substituted 4,5-diaryloxazole were prepared and evaluated for their ability to inhibit the inducible form of cyclooxygenase (COX-2) in vitro and in vivo. Several unique substitution patterns were identified that led to potent and selective inhibitors of COX-2. In general, 2-trifluoromethly-4,5-diaryloxazoles substituted with a methylsulfonyl or sulfonamido group were particularly potent inhibitors. One of the more potent compounds with a selectivity for COX-2 of about 800 fold was 4b (SC-299). SC-299, a highly fluorescent molecule, may be useful for spectroscopic studies on preferential inhibitor binding to COX-2.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase Inhibitors/pharmacology , Isoenzymes/drug effects , Oxazoles/pharmacology , Prostaglandin-Endoperoxide Synthases/drug effects , Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Humans , Membrane ProteinsSubject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Cyclooxygenase Inhibitors/therapeutic use , Isoenzymes/pharmacology , Prostaglandin-Endoperoxide Synthases/pharmacology , Arthritis/drug therapy , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Humans , Membrane Proteins , Structure-Activity RelationshipABSTRACT
The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. These lipid mediators play important roles in inflammation and pain and in normal physiological functions. While there are abundant data indicating that the inducible isoform, COX-2, is important in inflammation and pain, the constitutively expressed isoform, COX-1, has also been suggested to play a role in inflammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor, SC-560 (COX-1 IC50 = 0.009 microM; COX-2 IC50 = 6.3 microM). SC-560 inhibited COX-1-derived platelet thromboxane B2, gastric PGE2, and dermal PGE2 production, indicating that it was orally active, but did not inhibit COX-2-derived PGs in the lipopolysaccharide-induced rat air pouch. Therapeutic or prophylactic administration of SC-560 in the rat carrageenan footpad model did not affect acute inflammation or hyperalgesia at doses that markedly inhibited in vivo COX-1 activity. By contrast, celecoxib, a selective COX-2 inhibitor, was anti-inflammatory and analgesic in this model. Paradoxically, both SC-560 and celecoxib reduced paw PGs to equivalent levels. Increased levels of PGs were found in the cerebrospinal fluid after carrageenan injection and were markedly reduced by celecoxib, but were not affected by SC-560. These results suggest that, in addition to the role of peripherally produced PGs, there is a critical, centrally mediated neurological component to inflammatory pain that is mediated at least in part by COX-2.
Subject(s)
Arthritis, Experimental/enzymology , Cyclooxygenase Inhibitors/pharmacology , Inflammation/enzymology , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Pyrazoles/pharmacology , Animals , Blood Platelets/drug effects , Blood Platelets/metabolism , Carrageenan , Celecoxib , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Dinoprostone/metabolism , Edema , Hyperalgesia , Indomethacin/pharmacology , Male , Membrane Proteins , Models, Biological , Rats , Rats, Sprague-Dawley , Recombinant Proteins/metabolism , Sulfonamides/pharmacology , Thromboxane B2/bloodABSTRACT
A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
