CCR5 is a clinically proven target for inhibition of HIV-1 infection and a potential target for various inflammatory diseases. In this paper, we describe INCB9471, a potent and specific inhibitor of human CCR5 that has been proven to be safe and efficacious in viral load reduction in phase I and II human clinical trails. INCB9471 was identified using a primary human monocyte-based radioligand competition binding assay. It potently inhibited MIP-1beta-induced monocyte migration and infection of PBMCs by a panel of R5-HIV-1 strains. The results from binding and signaling studies using incremental amounts of INCB9471 demonstrated INCB9471 as a non-competitive CCR5 inhibitor. The CCR5 residues that are essential for interaction with INCB9471 were identified by site specific mutagenesis studies. INCB9471 rapidly associates with but slowly dissociates from CCR5. When INCB9471 was compared to three CCR5 antagonists that had been tested in clinical trials, the potency of INCB9471 in blocking CCR5 ligand binding was similar to those of SCH-D (vicriviroc), 873140 (aplaviroc) and UK427857 (maraviroc). Its inhibitory activity against CCR5-mediated Ca++ mobilization was also similar to those of SCH-D and 873140. Further analysis suggested that INCB9471 and UK427857 may have different binding sites on CCR5. The significance of two CCR5 antagonists with different binding sites is discussed in the context of potentially overcoming drug resistant HIV-1 strains.
- Received January 20, 2011.
- Revision received March 7, 2011.
- Accepted March 24, 2011.
- The American Society for Pharmacology and Experimental Therapeutics