Discovery of benzo[ g]indol-3-carboxylates as potent inhibitors of microsomal prostaglandin E 2 synthase-1

Abstract

Selective inhibition of pro-inflammatory prostaglandin (PG)E 2 formation via microsomal PGE 2 synthase-1 (mPGES-1) might be superior over inhibition of all cyclooxygenase (COX)-derived products by non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs. We recently showed that benzo[ g]indol-3-carboxylates potently suppress leukotriene biosynthesis by inhibiting 5-lipoxygenase. Here, we describe the discovery of benzo[ g]indol-3-carboxylates as a novel class of potent mPGES-1 inhibitors (IC 50 ⩾ 0.1 μM). Ethyl 2-(3-chlorobenzyl)-5-hydroxy-1 H-benzo[ g]indole-3-carboxylate (compound 7a) inhibits human mPGES-1 in a cell-free assay (IC 50 = 0.6 μM) as well as in intact A549 cells (IC 50 = 2 μM), and suppressed PGE 2 pleural levels in rat carrageenan-induced pleurisy. Inhibition of cellular COX-1/2 activity was significantly less pronounced. Compound 7a significantly reduced inflammatory reactions in the carrageenan-induced mouse paw edema and rat pleurisy. Together, based on the select and potent inhibition of mPGES-1 and 5-lipoxygenase, benzo[ g]indol-3-carboxylates possess potential as novel anti-inflammatory drugs with a valuable pharmacological profile.