Biaryl Diacid Inhibitors Of Human S-Pla(2) With Anti-Inflammatory Activity

Twenty-four hydrophobic dicarboxylic acids are described which were evaluated as inhibitors of 14 kDa human platelet phospholipase A(2) (HP-PLA(2)). In general, biarylacetic acid derivatives were found to be more active than biaryl acids or biaryl-propanoic 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-PLA(2). 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. (C) 2000 Elsevier Science Ltd. All rights reserved.