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The Discovery of Setileuton, a Potent and Selective 5-Lipoxygenase Inhibitor

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posted on 08.07.2010 by Yves Ducharme, Marc Blouin, Christine Brideau, Anne Châteauneuf, Yves Gareau, Erich L. Grimm, Hélène Juteau, Sébastien Laliberté, Bruce MacKay, Frédéric Massé, Marc Ouellet, Myriam Salem, Angela Styhler, Richard W. Friesen
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.

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