Structural optimization and biological evaluation of 2-substituted 5-hydroxyindole-3-carboxylates as potent inhibitors of human 5-lipoxygenase.

Abstract

Pharmacological suppression of leukotriene biosynthesis by inhibitors of 5-lipoxygenase (5-LO) is a strategy to intervene with inflammatory and allergic disorders. We recently presented 2-amino-5-hydroxy-1H-indoles as efficient 5-LO inhibitors in cell-based and cell-free assays. Structural optimization led to novel benzo[g]indole-3-carboxylates exemplified by ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 11a), which inhibits 5-LO activity in human neutrophils and recombinant human 5-LO with IC(50) values of 0.23 and 0.086 microM, respectively. Notably, 11a efficiently blocks 5-LO product formation in human whole blood assays (IC(50) = 0.83-1.6 microM) and significantly prevented leukotriene B(4) production in pleural exudates of carrageenan-treated rats, associated with reduced severity of pleurisy. Together, on the basis of their high potency against 5-LO and the marked efficacy in biological systems, these novel and straightforward benzo[g]indole-3-carboxylates may have potential as anti-inflammatory therapeutics.

• Authors: Eva-Maria Karg, Susann Luderer, Carlo Pergola, Ulrike Bühring, Antonietta Rossi, Hinnak Northoff, Lidia Sautebin, Reinhard Troschütz, Oliver Werz
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 11 Pg. 3474-83 (Jun 11 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19492852 (Publication Type: Journal Article)

Chemical References

• Indoles
• Lipoxygenase Inhibitors
• 5-hydroxyindole
• Carrageenan

Topics

• Animals
• Carrageenan
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Inhibitory Concentration 50
• Lipoxygenase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Neutrophils (drug effects)
• Pleurisy (chemically induced, drug therapy)
• Rats
• Structure-Activity Relationship