The discovery of setileuton, a potent and selective 5-lipoxygenase inhibitor

  • ACS Med Chem Lett. 2010 Apr 13;1(4):170-4. doi: 10.1021/ml100029k.
Yves Ducharme  1 ,  Marc Blouin  1 ,  Christine Brideau  1 ,  Anne Châteauneuf  1 ,  Yves Gareau  1 ,  Erich L Grimm  1 ,  Hélène Juteau  1 ,  Sébastien Laliberté  1 ,  Bruce MacKay  1 ,  Frédéric Massé  1 ,  Marc Ouellet  1 ,  Myriam Salem  1 ,  Angela Styhler  1 ,  Richard W Friesen  1
Affiliations
  • 1. Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
PMID: 24900191 DOI: 10.1021/ml100029k
Abstract

The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene Potassium Channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.

Keywords
Human 5-lipoxygenase; MK-0633; leukotriene biosynthesis; respiratory diseases; setileuton.
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