title: Biaryl diacid inhibitors of human s-PLA2 with anti-inflammatory activity.
abstract: 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.
authors.affiliation: Central Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Springer
authors.forename: B Y
authors.initials: BY
authors.lastname: Luh
authors.forename: J J
authors.initials: JJ
authors.lastname: Bronson
authors.forename: K E
authors.initials: KE
authors.lastname: McElhone
authors.forename: M M
authors.initials: MM
authors.lastname: Mansuri
authors.forename: K R
authors.initials: KR
authors.lastname: Gregor
authors.forename: D O
authors.initials: DO
authors.lastname: Nettleton
authors.forename: P L
authors.initials: PL
authors.lastname: Stanley
authors.forename: K M
authors.initials: KM
authors.lastname: Tramposch
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013057:Spectrum Analysis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D010741:Phospholipases A; D054467:Phospholipases A2