ABSTRACT
CL 306,293, a substituted quinoline carboxylic acid at a daily oral dose between 1.5 and 3.0 mg/kg suppressed the inflammation and joint destruction (radiological criteria) associated with both developing and established adjuvant arthritis. When a weekly oral dosing regimen was used, joint destruction was attenuated when this agent was administered at a dose of 50 to 200 mg/kg. Inflammation associated with a delayed type hypersensitivity reaction in dogs was suppressed at a daily dose of 0.25 mg/kg or a weekly dose of 1 mg/kg. At efficacious doses, CL 306,293 had no effects on cyclooxygenase or lipoxygenase activities nor did it have an effect on carrageenin induced paw edema. In acute tests, the compound was not ulcerogenic. The above observations indicate that the antiinflammatory effects of CL 306,293 are distinct from those observed with nonsteroidal antiinflammatory agents. Mechanistic studies conducted and to be published indicate that CL 306,293 down regulates T cell function and this mechanism may account, at least in part, for the antiinflammatory and antiarthritic properties observed in animal models of inflammation and joint destruction.
Subject(s)
Aminoquinolines/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Biphenyl Compounds/pharmacology , Administration, Oral , Aminoquinolines/administration & dosage , Aminoquinolines/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/pathology , Biphenyl Compounds/administration & dosage , Biphenyl Compounds/therapeutic use , Dogs , Dose-Response Relationship, Drug , Inflammation/drug therapy , Inflammation/pathology , Male , Rats , Rats, Inbred Strains , T-Lymphocytes/drug effectsABSTRACT
The synthesis of dl-11-doxy-15- or 16-alkylprostaglandins by the conjugate addition of appropriately substituted lithium alanate or lithium cuprate reagents to several cyclopentenones is described as is the preparation of the requisite intermediate (E)-1-iodo-1-alkenyl compounds 4, 22, 23, and 31. The bronchodilator activity of these prostaglandin congeners is presented.
Subject(s)
Bronchodilator Agents/chemical synthesis , Prostaglandins E, Synthetic/chemical synthesis , Animals , Female , Guinea Pigs , Male , Prostaglandins E, Synthetic/pharmacology , Structure-Activity RelationshipABSTRACT
Simplified prostaglandin analogs were prepared and tested for inhibition of gastric acid secretion. An alkyl moiety of 1-8 carbon atoms was substituted for the C-13 to C-20 chain of the PG's. Analog variations included shortened and lengthened acid side chains, beta-oxidation blockage, beta-ketol, Falpha-hydroxyl, and cyclohexanone substitution. Maximal inhibitory activity was obtained with the shorter alkyl moieties.