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2013-05-23 - Article/Dans un journal avec peer-review - Anglais - 16 page(s)

Soubhye Jalal, Aldib Iyas, Elfving Betina, Gelbcke Michel, Furtmuller Paul G., Podrecca Manuel , Conotte Raphael , Colet Jean-Marie , Rousseau Alexandre, Reyé Florence, Sarakbi A., Vanhaeverbeek Michel , Kauffmann Jean-Michel, Obinger Christian, Nève Jean, Prevost Martine, Zouaoui Boudjeltia Karim , Dufrasne François , Van Antwerpen P., "Design, Synthesis, and Structure-Activity Relationship Studies of Novel 3-Alkylindole Derivatives as Selective and Highly Potent Myeloperoxidase Inhibitors" in Journal of Medicinal Chemistry, 56, 10, 3943-3958, doi: 10.1021/jm4001538

  • Edition : American Chemical Society, Washington (DC)
  • Codes CREF : Sciences pharmaceutiques (DI3400), Chimie pharmaceutique (DI3413)
  • Unités de recherche UMONS : Biologie humaine et Toxicologie (M125), Chimie thérapeutique et Pharmacognosie (M136)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
Texte intégral :

Abstract(s) :

(Anglais) Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed.