CCR5 entry inhibitors are an emerging new class of antiretroviral drugs for the treatment of HIV infection. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising.

One CCR5 antagonist, aplaviroc from GlaxoSmithKline, is no longer in clinical development, due to the onset of severe liver toxicity is some patients. The CCR5 entry inhibitor maraviroc from Pfizer is entering Phase III development and could become the first oral entry inhibitor on the market.

In the current report, researchers describe a third novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), in development by Schering-Plough, with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist.

Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates.

In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication.

This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C.

Functional assays, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines.

Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects.

The authors conclude, “Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.”

01/13/06

Reference
J M Strizki and others. Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1. Antimicrobial Agents and Chemotherapy 49(12): 4911-4919. December 2005.

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