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

Citations Over Time

Abstract

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, 6d, 6e, 6i, 6h, and 6k, 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, 6d and 6h were selected for further development.

Related Papers

• → In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression(1997)632 cited
• → A quantitative assessment of hERG liability as a function of lipophilicity(2006)148 cited
• → Interaction of Chemokine Receptor CCR5 with its Ligands: Multiple Domains for HIV-1 gp120 Binding and a Single Domain for Chemokine Binding(1997)357 cited
• → CCR5 Has an Expanded Ligand-Binding Repertoire and Is the Primary Receptor Used by MCP-2 on Activated T Cells(1998)87 cited
• → Crystal structure of Selzentry maraviroc–bound HIV-1 co-receptor CC chemokine receptor 5 (CCR5; CD195)(2013)