title: 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.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Marc
authors.initials: M
authors.lastname: Blouin
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Anne
authors.initials: A
authors.lastname: Châteauneuf
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Yves
authors.initials: Y
authors.lastname: Gareau
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Erich L
authors.initials: EL
authors.lastname: Grimm
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Hélène
authors.initials: H
authors.lastname: Juteau
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Laliberté
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Bruce
authors.initials: B
authors.lastname: MacKay
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Massé
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Marc
authors.initials: M
authors.lastname: Ouellet
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Myriam
authors.initials: M
authors.lastname: Salem
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Angela
authors.initials: A
authors.lastname: Styhler
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Friesen
keywords: Human 5-lipoxygenase; MK-0633; leukotriene biosynthesis; respiratory diseases; setileuton