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Antimicrobial Agents and Chemotherapy, December 2005, p. 4911-4919, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4911-4919.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1

Departments of Antiviral Therapy,¹ Inflammation,³ Medicinal Chemistry,⁴ Drug Metabolism and Pharmacokinetics,⁵ Neurobiology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033,⁶ Infectious Disease Division, Department of Medicine, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114,² Monogram Biosciences, 345 Oyster Point Boulevard, South San Francisco, California 94080⁷

Received 14 April 2005/ Returned for modification 7 July 2005/ Accepted 27 September 2005

Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), 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, including inhibition of calcium flux, guanosine 5'-[³⁵S]triphosphate exchange, and chemotaxis, 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. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.

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