化合物信息

Description

Immunology , Infection

Description

Vicriviroc (SCH-417690, SCH-D) is a potent CCR5 inhibitor with IC50 of 0.91 nM.

Targets

IC₅₀

In Vitro

Vicriviroc binds with higher affinity to CCR5 versus SCH-C (SCH-351125) in competition binding assays with K_i value of 0.8 nM versus 2.6 nM. Vicriviroc is nearly 6-fold less active than SCH-C (IC50 = 5.8 μM versus 1.1 μM) in attenuating hERG current among voltage-clamped L929 cells, indicating a reduced potential for cardiac effects. Vicriviroc inhibits MIP-1α induced migration of Ba/F3 cells stably expressing recombinant human CCR5, with IC50 of 0.91 nM. In U-87-CCR5 cells, Vicriviroc inhibits intracellular calcium release induced by the ligand RANTES with IC50 of 16 nM, while Vicriviroc treatment alone does not stimulate the release of calcium. Vicriviroc inhibits GTPγS binding to the membranes from HTS-hCCR5 cells induced by RANTES, with IC50 of 4.2 nM. Vicriviroc displays potent antiviral activity against a panel of 30 R5-tropic HIV-1 isolates representing diverse genetic clades, with EC50 values ranging from 0.04 nM to 2.3 nM, and EC90 from 0.45 nM to 18 nM, being more potent (2- to 40-fold) than SCH-C. Vicriviroc is also highly active against a Clade G Russian isolate RU570 with EC90 of 16 nM, which is resistant to inhibition by SCH-C (EC90 > 1 μM). Vicriviroc could target an early step in the viral life cycle prior to reverse transcription and virion maturation, the targets of reverse transcriptase inhibitor and protease inhibitor, respectively. Consistent with the selectivity for CCR5, Vicriviroc is not active against viruses capable of using the CXCR4 coreceptor (R5/X4 or X4 tropic) for infection. ^[1]

In Vivo

Clinical Trials

A Phase II study to evaluate the safety and efficacy of three different doses of Vicriviroc in HIV infected patients has been completed. A Phase I/II study to evaluate the pharmacokinetics, safety, tolerability and antiviral activity of Vicriviroc in combination with a ritonavir boosted protease inhibitor containing background regimen in HIV-infected antiretroviral treatment experienced children and adolescents has been completed.

Features

Description

Vicriviroc demonstrates synergistic anti-HIV activity in combination with Zidovudine, Lamivudine, Efavirenz, Indinavir, or Enfuvirtide. ^[1]

Chemotaxis assay

Ba/F3-CCR5 cells in chemotaxis buffer (RPMI supplemented with 1% FBS and 0.1 μg/mL mouse IL-3) are pretreated for 1 hour with increasing concentrations of Vicriviroc at 37 °C. Chemotaxis buffer containing Vicriviroc and MIP-1α (0.3 nM), MIP-1β (0.3 nM), or RANTES (0.3 nM) is placed into the bottom well of a 5-μm ChemoTx plate, and the filter unit is placed over the wells. Ba/F3-CCR5 cells pretreated with Vicriviroc are pipetted (25 μL) onto the filters, and the plate is incubated at 37 °C for 2 hours. Unmigrated cells are scraped off the filter, and the plate is centrifuged to pellet-migrated cells. Cells are then transferred to a Microlite 1⁺ Flatbottom Microtiter plate and quantitated using the Cell Titer Glow luminescent cell viability assay kit. IC50 value for Vicriviroc is calculated using GraphPad Prism Software.