CCR5; HIV-1; CCR5 ( Ki = 2.5 nM ); HIV-1 (301657) ( IC90 = 1.8 nM ); HIV-1 (ADA-M) ( IC90 = 2.8 nM ); HIV-1 (JrFL) ( IC90 = 3.3 nM ); HIV-1 (JV1083) ( IC90 = 4.9 nM ); HIV-1 (RU 570) ( IC90 = 10 nM )
Vicriviroc is a small-molecule antagonist of the C-C chemokine receptor type 5 (CCR5). Its binding affinity (Ki) to CCR5, determined by equilibrium competitive binding assays using [³H]SCH-C, is approximately 0.8 nM. [2]

Vicriviroc maleate (SCH-417690 maleate; SCH-D maleate) inhibits HIV-1 in PBMC cells with IC90s of 3.3 (JrFL), 2.8 (ADA-M), 1.8 (301657), 4.9 (JV1083), and 10 nM (RU 570). It is a strong, selective, and oral bioavailable inhibitor of CCR5. Furthermore, Vicriviroc maleate exhibits weak activity against hERG activity (IC50, 5.8 μM) and has mean IC50 and IC90 values of 0.45 nM and 4 nM for a panel of HIV isolates[1]. Vicriviroc maleate suppresses RANTES-induced signaling with a mean IC50 of 4.2 ± 1.3 nM and inhibits the chemotactic response to MIP-1α with IC50 values below 1 nM. Vicriviroc maleate, with geometric mean EC50s of 0.04-2.3 nM and IC90s of 0.45-18 nM, potently suppresses all the tested viral isolates[2].

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Vicriviroc potently inhibited replication of a diverse panel of 30 RS-tropic (CCR5-using) HIV-1 primary isolates from various genetic clades in human peripheral blood mononuclear cell (PBMC) infection assays. The geometric mean 50% effective concentrations (EC50) ranged from 0.04 nM to 2.3 nM, and EC90 values ranged from 0.45 nM to 18 nM. [2]
In head-to-head comparisons, Vicriviroc was consistently 2- to 40-fold more potent than the earlier CCR5 antagonist SCH-C against multiple HIV-1 isolates. It also showed potent activity against a Clade G isolate (RU570) that had reduced susceptibility to SCH-C. [2]
Vicriviroc demonstrated broad-spectrum activity against HIV-1 pseudoviruses engineered to carry reverse transcriptase inhibitor (RTI), protease inhibitor (PI), or multi-drug resistance (MDR) mutations, as well as against viruses with enfuvirtide (fusion inhibitor) resistance mutations (V38A or G36D/V38M in gp41). The EC50 values against these resistant viruses were comparable (less than 2-fold change) to the wild-type control virus. [2]
In combination studies with other antiretroviral agents, Vicriviroc showed synergistic antiviral activity (Combination Index, CI < 0.9) at effective concentrations with zidovudine, lamivudine, efavirenz, indinavir, and enfuvirtide. [2]
Vicriviroc acted as a pure antagonist of CCR5, potently inhibiting CCR5-mediated functional responses. It inhibited MIP-1α-induced chemotaxis of Ba/F3-CCR5 cells with an IC50 below 1 nM. It inhibited RANTES-induced calcium flux in U-87-CCR5 cells with potency similar to SCH-C. It inhibited RANTES-stimulated guanosine 5'-[³⁵S]triphosphate ([³⁵S]GTPγS) exchange in CCR5-expressing membranes with a mean IC50 of 4.2 ± 1.3 nM. In all functional assays, Vicriviroc alone did not activate CCR5 signaling, confirming its antagonist properties. [2]

Vicriviroc maleate (SCH-417690 maleate; SCH-D maleate; 10 mg/kg) does not cause acute CNS or GI side effects in rats and exhibits good oral availability in both monkeys and rats[1].

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The paper references a previous clinical trial with the earlier compound SCH-C which demonstrated antiviral activity in HIV-1 infected patients. [2]

Radioligand competitive binding assays were performed using scintillation proximity assay (SPA) technology. Membranes from HTS-1 cells expressing human CCR5 were pre-incubated with wheat germ agglutinin-coated SPA beads in binding buffer. The beads and membranes were transferred to a plate and incubated with a fixed concentration of [³H]SCH-C and specified dilutions of unlabeled Vicriviroc or SCH-C. Radioligand binding to the membranes was measured by scintillation counting. Competition binding analyses were conducted to calculate compound affinities (Ki) from binding IC50 values using the Cheng-Prusoff equation. Saturation binding analysis with [³H]SCH-C was also performed to determine its equilibrium dissociation constant (Kd). [2]

For three to seven days, ficoll-purified peripheral blood mononuclear cells (PBMCs) are stimulated in vitro with 50 U/mL of interleukin-2 (IL-2) and 5 μg/mL of phytohemagglutinin (PHA). Following a 1-hour incubation period at 37°C with an equal volume of culture medium containing compound (Vicriviroc), the cells are resuspended at 4 × 10⁶/mL in complete medium (RPMI, 10% fetal bovine serum [FBS], 50 U/mL IL-2), seeded into 96-well plates (2 × 10⁵/well), and infected in triplicate using 25 to 100 50% tissue culture infectious doses (TCID50) per well of viral inoculum for three to four hours. After two rounds of washing in phosphate-buffered saline (PBS) to get rid of any remaining virus, the cells are cultured in the compound for four to six days. The extracellular p24 antigen in the supernatants is measured using an enzyme-linked immunosorbent assay to determine the amount of HIV-1 replication. With Graphpad PRISM software, the 50% effective concentrations (EC50s) and EC90s for each virus are calculated[2].

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Phytohemagglutinin (PHA) and interleukin-2 (IL-2) stimulated human PBMCs were seeded into plates and pre-incubated with serial dilutions of Vicriviroc for 1 hour at 37°C. Cells were then infected in triplicate with a defined amount of HIV-1 viral inoculum for 3-4 hours. After washing to remove residual virus, cells were cultured in the continued presence of the compound for 4-6 days. HIV-1 replication was quantified by measuring extracellular p24 antigen in the culture supernatants using an enzyme-linked immunosorbent assay. The 50% and 90% effective concentrations (EC50 and EC90) for each virus were determined using curve-fitting software. [2]
Cell Assay (PhenoSense HIV Entry Assay): Recombinant pseudoviruses, carrying HIV-1 envelope genes from RS-tropic isolates and either wild-type or drug-resistant reverse transcriptase/protease genes, were generated by cotransfecting cells. Virus stocks were used to inoculate US7-CD4-CCR5 target cells in the presence or absence of serial dilutions of Vicriviroc. Infection was quantified 72 hours later by measuring luciferase activity in target cell lysates. Inhibition was calculated, and dose-response curves were plotted to determine EC50 values. [2]
Cell Assay (Calcium Flux Assay): U-87 cells expressing human CCR5 were plated and loaded with a calcium-sensitive fluorescent dye (Fluo-4) in a buffer. After washing, serial dilutions of Vicriviroc were added to the cells, and baseline fluorescence was read. Subsequently, a chemokine agonist (e.g., RANTES, MIP-1α, MIP-1β) was added to stimulate CCR5, and the change in fluorescence (calcium signal) was immediately measured. The percent inhibition of calcium flux was calculated, and IC50 values were determined. [2]
Cell Assay (Chemotaxis Assay): Ba/F3 cells stably expressing human CCR5 were pretreated with decreasing concentrations of Vicriviroc for 1 hour. Chemotaxis buffer containing the compound and a chemokine agonist (MIP-1α, MIP-1β, or RANTES) was placed in the bottom chamber of a chemotaxis plate. The pretreated cells were added to the top chamber filter. After incubation, non-migrated cells were scraped off, and migrated cells pelleted in the bottom chamber were quantified using a luminescent cell viability assay. IC50 values for inhibition of migration were calculated. [2]
Cell Assay ([³⁵S]GTPγS Binding Assay): Membranes expressing CCR5 were pre-incubated with wheat germ agglutinin-coated SPA beads in binding buffer. The bead-membrane mixture was transferred to a plate and incubated with Vicriviroc for 24 hours at 4°C. The incubation was continued at room temperature with guanosine diphosphate (GDP) and a chemokine agonist (RANTES). Finally, [³⁵S]GTPγS was added. Membrane-bound [³⁵S]GTPγS was measured using a scintillation counter. Inhibition of agonist-stimulated binding was calculated to determine IC50. [2]

To evaluate pharmacokinetic properties, male rats (groups of three) were dosed with [³H]Vicriviroc at 10 mg/kg body weight either intravenously (i.v.) or by oral gavage. Cynomolgus monkeys (three fasted males) were dosed with the compound at 2 mg/kg via i.v. or oral routes. For oral dosing, the compound was dissolved in 0.4% methylcellulose. For i.v. dosing, it was dissolved in 20% hydroxypropyl-β-cyclodextrin. Following administration, plasma samples were collected periodically over 24 hours. Plasma concentrations of the parent compound were determined using high-performance liquid chromatography tandem mass spectrometry. Total radioactivity was measured by scintillation counting. Pharmacokinetic parameters such as area under the curve (AUC), maximum plasma concentration (Cmax), half-life, absorption, and bioavailability were calculated from the concentration-time profiles. [2]

In rats, the absorption rate of 10 mg/kg of vicriviroc was 100%, and the oral bioavailability was 100%. In cynomolgus monkeys, the absorption rate of 2 mg/kg of vicriviroc was 95%, and the oral bioavailability was 89%. [2]
The peak plasma concentration (Cmax) after oral administration of 2 mg/kg to monkeys was 1.3 μM. [2]
The plasma half-life of vicriviroc in rats was 7.9 hours, and the plasma half-life in cynomolgus monkeys was 3.4 hours. [2]
Studies on human liver microsomal metabolism showed that vicriviroc had no significant inhibitory effect on key cytochrome P450 enzymes (CYP2D6, CYP3A4, CYP2C9, CYP2C19, CYP1A2), with an IC50 value >30 μM. [2]
Vicriviroc has moderate plasma protein binding in human plasma, with approximately 16% of the compound existing in free form. In cell culture, the presence of up to 50% human serum does not affect its antiviral activity. [2]

In whole-cell voltage-clamp experiments using mouse L-929 cells stably expressing the human ether-a-go-go related gene (hERG) potassium channel, vicriviroc showed an IC50 of 5.8 μM for inhibiting hERG current. This value is approximately 5.3 times higher than the IC50 of SCH-C in the same experiment (1.1 μM), suggesting lower potency and a lower likelihood that vicriviroc would cause QTc interval prolongation in the heart. [2]
In preclinical animal models, vicriviroc was well tolerated at the tested dose. Electrocardiographic studies in monkeys and dogs showed that vicriviroc had no effect on the QTc interval at plasma concentrations up to 3.6 μM and 6 μM, respectively. [2]
No significant cytotoxicity was observed in uninfected PBMC cultures treated with vicriviroc at concentrations up to 10 μM. [2]

[1]. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]- 4-[4-[2-methoxy-1(R)-4-(trifluoromethyl)phenyl]ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist. J Med Chem. 2004 May 6;47(10):2405-8.

[2]. Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2005 Dec;49(12):4911-9.

Vicriviroc maleate is the maleate form of veviciverone, a piperazine CCR5 receptor antagonist with anti-human immunodeficiency virus (HIV) activity. Vicriviroc is designed to bind to CCR5 and inhibit HIV entry into CD4 cells.

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Drug indication
Treatment of human immunodeficiency virus (HIV-1) infection

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Vicriviroc (formerly known as SCH-D, SCH 417690) is a second-generation, orally bioavailable small molecule CCR5 antagonist being developed as a clinical candidate for the treatment of HIV-1 infection. [2]
Its mechanism of action is to specifically bind to the CCR5 co-receptor on host cells, preventing it from interacting with the HIV-1 envelope glycoprotein gp120, thereby blocking viral entry into cells. [2]
The compound was chosen because of its enhanced antiviral efficacy, excellent pharmacokinetic properties (high absorption and bioavailability), and reduced affinity for hERG ion channels compared to the prototype CCR5 antagonist SCH-C. [2]

C32H42F3N5O6

649.70098

649.308

C, 59.16; H, 6.52; F, 8.77; N, 10.78; O, 14.77

599179-03-0

306296-47-9; 541503-81-5 (malate); 599179-03-0; 541503-48-4 (HCl)

6451165

White to beige solid powder

608.1ºC at 760mmHg

4.026

2

13

8

46

892

2

CC1(N2C[C@H](C)N([C@H](C3=CC=C(C(F)(F)F)C=C3)COC)CC2)CCN(C(C4=C(C)N=CN=C4C)=O)CC1.O=C(O)/C=C\C(O)=O

GXINKQQWHLIBJA-UCIBKFKQSA-N

InChI=1S/C28H38F3N5O2.C4H4O4/c1-19-16-35(14-15-36(19)24(17-38-5)22-6-8-23(9-7-22)28(29,30)31)27(4)10-12-34(13-11-27)26(37)25-20(2)32-18-33-21(25)3;5-3(6)1-2-4(7)8/h6-9,18-19,24H,10-17H2,1-5H3;1-2H,(H,5,6)(H,7,8)/b;2-1-/t19-,24-;/m0./s1

(Z)-but-2-enedioic acid;(4,6-dimethylpyrimidin-5-yl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl]methanone

SCH417690; SCH 417690; SCH-417690; SCH-D

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 50~100 mg/mL (77~149.8 mM)
Water: ~100 mg/mL
Ethanol: ~100 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.85 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.85 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.85 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)