Mitigating hERG Inhibition:
Design of Orally Bioavailable
CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication

Skerlj, Renato; Bridger, Gary; Zhou, Yuanxi; Bourque, Elyse; McEachern, Ernest; Danthi, Sanjay; Langille, Jonathan; Harwig, Curtis; Veale, Duane; Carpenter, Bryon; Ba, Tuya; Bey, Michael; Baird, Ian; Wilson, Trevor; Metz, Markus; MacFarland, Ron; Mosi, Renee; Bodart, Veronique; Wong, Rebecca; Fricker, Simon; Huskens, Dana; Schols, Dominique

doi:10.1021/ml2002604.s001

ml2002604_si_001.pdf (104.35 kB)

Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication

journal contribution

posted on 2012-03-08, 00:00 authored by Renato Skerlj, Gary Bridger, Yuanxi Zhou, Elyse Bourque, Ernest McEachern, Sanjay Danthi, Jonathan Langille, Curtis Harwig, Duane Veale, Bryon Carpenter, Tuya Ba, Michael Bey, Ian Baird, Trevor Wilson, Markus Metz, Ron MacFarland, Renee Mosi, Veronique Bodart, Rebecca Wong, Simon Fricker, Dana Huskens, Dominique Schols

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.