Biaryl diacid inhibitors of human s-PLA2 with anti-inflammatory activity

• Published in: Bioorganic & medicinal chemistry Vol. 8; no. 5; pp. 1087 - 1109
• Main Authors: SPRINGER, D. M, LUH, B.-Y, BRONSON, J. J, MCELHONE, K. E, MANSURI, M. M, GREGOR, K. R, NETTLETON, D. O, STANLEY, P. L, TRAMPOSCH, K. M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 01.05.2000
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - enzymology; Bones, joints and connective tissue. Antiinflammatory agents; Dicarboxylic Acids - chemistry; Dicarboxylic Acids - pharmacology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Medical sciences; Mice; Pharmacology. Drug treatments; Phospholipases A - antagonists & inhibitors; Phospholipases A2; Spectrum Analysis; Ether; Enzyme; Antiinflammatory agent; Enzyme inhibitor; Esterases; Inflammation; In vitro; Phospholipase A; Carboxylic ester hydrolases; In vivo; Experimental disease; Structure activity relation; Biphenyl derivatives; Animal; Ear; Hydrolases; Benzenic compound; Dicarboxylic acid; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)00047-X

Twenty-four hydrophobic dicarboxylic acids are described which were evaluated as inhibitors of 14 kDa human platelet phospholipase A2 (HP-PLA2). In general, biarylacetic acid derivatives were found to be more active than biaryl acids or biarylpropanoic acids. More potent inhibitors were obtained when hydrophobic groups were attached to the biaryl acid nucleus using an olefin linkage as compared to an ether linkage. Compounds with larger hydrophobic groups were usually more potent inhibitors of HP-PLA2. Five of the compounds disclosed in this report (2, 4, 28, 36b and 36i) were found to possess significant anti-inflammatory activity in a phorbol ester induced mouse ear edema model of chronic inflammation.