title: Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication.
abstract: A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels.
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Renato
authors.initials: R
authors.lastname: Skerlj
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Bridger
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Yuanxi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Elyse
authors.initials: E
authors.lastname: Bourque
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Ernest
authors.initials: E
authors.lastname: McEachern
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Danthi
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Langille
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Curtis
authors.initials: C
authors.lastname: Harwig
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Duane
authors.initials: D
authors.lastname: Veale
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Bryon
authors.initials: B
authors.lastname: Carpenter
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Tuya
authors.initials: T
authors.lastname: Ba
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Bey
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Baird
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Trevor
authors.initials: T
authors.lastname: Wilson
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Markus
authors.initials: M
authors.lastname: Metz
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Ron
authors.initials: R
authors.lastname: MacFarland
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Renee
authors.initials: R
authors.lastname: Mosi
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Veronique
authors.initials: V
authors.lastname: Bodart
authors.affiliation: Anormed Inc. , 200-20353 64th Avenue, Langley, British Columbia, V2Y 1N5 Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wong
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Fricker
authors.affiliation: Rega Institute for Medical Research, Katholieke Universitett Leuven , Minderbroedersstraat 10, B-3000, Belgium.
authors.forename: Dana
authors.initials: D
authors.lastname: Huskens
authors.affiliation: Rega Institute for Medical Research, Katholieke Universitett Leuven , Minderbroedersstraat 10, B-3000, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
keywords: CCR5; HIV-1; chemokine receptor; hERG