title: Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1.
abstract: 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.
authors.affiliation: Department of Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, K15, E405C/4945, Kenilworth, New Jersey 07033, USA. Julie.strizki@spcorp.com
authors.forename: Julie M
authors.initials: JM
authors.lastname: Strizki
authors.forename: Cecile
authors.initials: C
authors.lastname: Tremblay
authors.forename: Serena
authors.initials: S
authors.lastname: Xu
authors.forename: Lisa
authors.initials: L
authors.lastname: Wojcik
authors.forename: Nicole
authors.initials: N
authors.lastname: Wagner
authors.forename: Waldemar
authors.initials: W
authors.lastname: Gonsiorek
authors.forename: R William
authors.initials: RW
authors.lastname: Hipkin
authors.forename: Chuan-Chu
authors.initials: CC
authors.lastname: Chou
authors.forename: Catherine
authors.initials: C
authors.lastname: Pugliese-Sivo
authors.forename: Yushi
authors.initials: Y
authors.lastname: Xiao
authors.forename: Jayaram R
authors.initials: JR
authors.lastname: Tagat
authors.forename: Kathleen
authors.initials: K
authors.lastname: Cox
authors.forename: Tony
authors.initials: T
authors.lastname: Priestley
authors.forename: Steve
authors.initials: S
authors.lastname: Sorota
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Martin
authors.initials: M
authors.lastname: Hirsch
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Reyes
authors.forename: Bahige M
authors.initials: BM
authors.lastname: Baroudy
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010879:Piperazines; D011743:Pyrimidines; C486781:vicriviroc