The discovery of CCR5 receptor antagonists for the treatment of HIV infection: Hit-to-lead studies

The discovery of UK-374,503 started from a high-throughput screening hit that was a potent Type II P450 2D6 inhibitor and which displayed no antiviral activity. The optimisation of affinity for the CCR5 receptor while reducing concerns about P450 inhibition and the subsequent introduction of antiviral effects were key milestones for the project.