| In vitro study | In competitive binding experiments, Vicriviroc had a higher affinity for CCR5 than for SCH-C(SCH 351125), with K I values of 0.8 nM versus 2.6 nM. Vicriviroc acts on voltage-clamped L929 cells, and the ability to attenuate hERG current is about 6 times weaker than SCH-C (IC50=5.8 μm Vs. 1.1 μm), indicating that the influence on the heart is reduced. Vicriviroc inhibited MIP-1α-induced migration of Ba/F3 cells stably expressing recombinant human CCR5 with an IC50 of 0.91 nM. Vicriviroc acts on U-87-CCR5 cells and inhibits intracellular ligand RANTES-induced calcium release with an IC50 of 16 nM, whereas without ligand induction, Vicriviroc alone does not stimulate calcium release. Vicriviroc inhibited gtpγs binding to RANTES-induced HTS-hCCR5 cell membrane with an IC50 of 4.2 nM. Vicriviroc has potent antiviral activity against a group of 30 R5 thermophilic HIV-1 isolates representing different genetic branches with an EC50 of 0.04 nM to 2.3 nM and an EC90 of 0.45 nM to 18 nM, 2 to 40 times more effective than SCH-C. Vicriviroc was also highly effective on the Clade G Russian isolate RU570, with an EC90 of 16 nM, Inhibitory effect of RU570 against SCH-C(EC90 >1 μm). Vicriviroc targets the Virus prophase of the life cycle prior to reverse transcription and Virus particle maturation, which are targets for reverse transcriptase inhibitors and protease inhibitors, respectively. Consistent with selective action on CCR5, Vicriviroc was inactive in Virus of infections using CXCR4 co-receptors (R5/X4 or X4 thermophilic). |
