2. Academic Validation
  3. Discovery of benzo[g]indol-3-carboxylates as potent inhibitors of microsomal prostaglandin E(2) synthase-1

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

  • Bioorg Med Chem. 2009 Dec 1;17(23):7924-32. doi: 10.1016/j.bmc.2009.10.025.
Andreas Koeberle 1,  Eva-Maria Haberl,  Antonietta Rossi,  Carlo Pergola,  Friederike Dehm,  Hinnak Northoff,  Reinhard Troschuetz,  Lidia Sautebin,  Oliver Werz
Affiliations

Affiliation

  • 1 Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany.
PMID: 19884011 DOI: 10.1016/j.bmc.2009.10.025
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 microM). Ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 7a) inhibits human mPGES-1 in a cell-free assay (IC(50)=0.6 microM) as well as in intact A549 cells (IC(50)=2 microM), 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.

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