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

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.

SUBMITTER: Ducharme Y

PROVIDER: S-EPMC4007958 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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

Ducharme Yves Y Blouin Marc M Brideau Christine C Châteauneuf Anne A Gareau Yves Y Grimm Erich L EL Juteau Hélène H Laliberté Sébastien S MacKay Bruce B Massé Frédéric F Ouellet Marc M Salem Myriam M Styhler Angela A Friesen Richard W RW

ACS medicinal chemistry letters 20100413 4

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 d ...[more]

PMID: 24900191

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