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 Bey, Michael Baird, Ian Wilson, Trevor Metz, Markus MacFarland, Ron Mosi, Renee Bodart, Veronique Wong, Rebecca Fricker, Simon Huskens, Dana Schols, Dominique #
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.