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

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

Design of Substituted Imidazolidinylpiperidinylbenzoic Acids as Chemokine Receptor 5 Antagonists: Potent Inhibitors of R5 HIV‑1 Replication

The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure–activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, <b>6d</b>, <b>6e</b>, <b>6i</b>, <b>6h</b>, and <b>6k</b>, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, <b>6d</b> and <b>6h</b> were selected for further development