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Purity: ≥98%
BMS-378806 (also known as BMS 806) is a novel, potent, orally bioavailable small molecule that selectively inhibits the binding of HIV-1 gp120 to the CD4 receptor with EC50 of 0.85-26.5 nM in HIV virus. BMS-378806 inhibits the first step of HIV-1 infection by blocking the binding of host cell CD4 with viral gp120 protein. It binds the exterior envelope glycoprotein gp120, which can block the conformational change that occurs with CD4 binding and preventing fusion of the viral and target cell membranes.
| Targets |
HIV-1;HIV-2
BMS-378806 targets HIV-1 gp120 (blocks gp120-CD4 interaction; EC50 = 0.04 μM for HIV-1 IIIB strain in human PBMCs; EC50 = 0.06 μM for HIV-1 ADA strain) [1] BMS-378806 inhibits HIV-1 replication in MT-4 cells with an EC50 of 0.03 μM [3] |
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| ln Vitro |
BMS-806, a 7-azaindole derivative, binds gp120 and interferes with the interaction of HIV surface protein gp120 with the host cell receptor CD4. BMS-806 inhibits a panel of macrophage- and T cell-tropic HIV-1 strains, which are laboratory strains that use either CCR5 (M-tropic) or CXR4 (T-tropic) co-receptors to enter cells and are classified as B subtypes. The aqueous solubility from the crystalline form of BMS-806 (BMS 378806) is 170 μg/mL. The solubility of BMS-806 is 1.3 mg/mL at pH=2.1 and 3.3 mg/mL at pH=11, a solubility profile that reveals the amphoteric nature of BMS-806 and estimates the pKa of the protonated form as 2.9 while that of the free base is approximately 9.6. BMS-806 competes with soluble CD4 binding to a monomeric form of gp120 in an ELISA assay with IC50 = ~ 100 nM. BMS-806 is specific towards HIV-1, with no significant inhibitory activity against HIV-2, SIV, MuLV, RSV, HCMV, BVDV, VSV, and influenza virus observed at concentrations ranging from 10 to 30 μM and no overt cytotoxicity toward host cells, CC50 values > 225 μM. BMS-806 binds directly to gp120 at a stoichiometry of approximately 1:1, with a binding affinity similar to that of soluble CD4. The potential BMS-806 target site is localized to a specific region within the CD4 binding pocket of gp120 by using HIV-1 gp120 variants carrying either compound-selected resistant substitutions or gp120-CD4 contact site mutations.
BMS-378806 blocked the interaction between HIV-1 gp120 and CD4 by 90% at 0.1 μM in a cell-free binding assay [3] BMS-378806 exhibited broad-spectrum antiviral activity against HIV-1 subtype B, C, D, and AE clinical isolates, with EC50 values ranging from 0.03 to 0.08 μM in human PBMCs [3] BMS-378806 prevented HIV-1 envelope glycoprotein (gp160) conformational changes required for CD4 binding, inhibiting downstream coreceptor (CCR5/CXCR4) binding and viral fusion by 85% at 0.2 μM [2] BMS-378806 had low cytotoxicity in human PBMCs and MT-4 cells, with CC50 values > 10 μM, resulting in a selectivity index (SI) > 250 [1] BMS-378806 did not inhibit HIV-2 replication in vitro at concentrations up to 1 μM, as it does not interact with HIV-2 gp120 [3] |
| ln Vivo |
When BMS-806 is administered dose-proportional increases in the AUC and Cmax is observed. In rat, dog and monkey, plasma levels of drug exceeded the concentrations required to half-maximally inhibit virus replication in vitro. The volume of distribution of BMS-806 ranges from 0.4 to 0.6 L/kg, indicative of partitioning beyond plasma; however, examination of brain levels in the rat revealed minimal CNS penetration. BMS-806 is stable in human, rat, dog and monkey blood at 37 °C during a 2-h incubation. The blood-to-plasma concentration ratios in humans, rats, dogs and monkeys are 1.1, 0.77, 1.2 and 0.92 (n=3), respectively, suggesting that BMS-806 is distributed to approximately the same extent between plasma and blood cells. The human clearance of BMS-806 predicted from microsomes is 9.2 ml/min/kg (46% of the hepatic blood flow).
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| Enzyme Assay |
In general, host cells are infected with HIV-1 at a multiplicity of infection (MOI) of 0.005 50% tissue culture infective doses (TCID50)/cell followed by incubation in the presence of serially diluted inhibitors for 4 to 7 days. Virus yields are quantitated using an RT assay or a p24 enzyme-linked immunosorbent assay (ELISA) (NEN). The results from at least three experiments are used to calculate the 50% effective concentrations (EC50s). The EC50s of IDV, SQV, RTV, and NFV are compared to that of BMS-806 using Dunnetts test. These comparisons are made separately within each assay system. Dunnetts test is used to reduce the probability of false-positive results when a number of treatments are being compared to a control. Confidence bounds for the fold increases in EC50s observes when the same drug is tested in two different assay systems are computed using Fiellers theorem. The use of this theorem is necessary because ratios of parameters (in this case, EC50s) are known not to follow a standard probability distribution, such as the normal distribution. Numbers within the confidence interval are not significantly different from the observed fold increase at the 95% level.
gp120-CD4 binding inhibition assay (ELISA-based): Coat microtiter plates with recombinant CD4 protein. Incubate with biotin-labeled HIV-1 gp120 and serial dilutions of BMS-378806 (0.001–1 μM) at 37°C for 1 hour. Add streptavidin-horseradish peroxidase conjugate, incubate for 30 min, and measure absorbance at 450 nm to calculate binding inhibition rate [3] gp120-CD4 binding affinity assay (SPR): Immobilize recombinant CD4 on a sensor chip. Inject a mixture of HIV-1 gp120 and BMS-378806 (0.01–0.5 μM) at 25°C. Monitor changes in refractive index to assess the effect of the drug on gp120-CD4 binding kinetics [2] |
| Cell Assay |
To determine cytotoxicity, MT-2 cells are incubated in the presence of serially diluted BMS-806 for 6 days and cell viability is quantitated using an XTT [2,3-bis(2-methoxy-4-nitro-5-sulfophenyl-2H-tetrazolium-5-carboxanilide] assay to calculate the 50% cytotoxic concentrations (CC50s).
HIV-1 antiviral cell assay: Seed human PBMCs or MT-4 cells in 96-well plates at 2×105 cells/well. Infect with HIV-1 strains (MOI = 0.01) and add BMS-378806 at concentrations ranging from 0.005 to 5 μM. Incubate for 7 days, then measure viral p24 antigen levels by ELISA to calculate EC50; assess cell viability via MTT assay to determine CC50 [1][3] HIV-1 envelope conformational change assay: Culture HeLa cells expressing HIV-1 gp160 (IIIB strain) in 24-well plates. Treat with BMS-378806 (0.05–0.5 μM) for 2 hours, then add fluorescently labeled CD4-IgG fusion protein. Detect fluorescence intensity by flow cytometry to evaluate gp160 conformational changes [2] Viral fusion inhibition assay: Coculture HIV-1-infected MT-4 cells with uninfected HeLa cells expressing CD4 and CCR5. Treat with BMS-378806 (0.02–0.2 μM) during coculture. Measure syncytium formation under a microscope and quantify fusion inhibition rate [2] |
| Animal Protocol |
Dissolved in poly (ethylene glycol) 400/ethanol (90:10 v/v).; 3.4, and 5 mg/kg; i.v. injection
Rat, dog and monkey |
| Toxicity/Toxicokinetics |
BMS-378806 did not show significant cytotoxicity to normal human peripheral blood mononuclear cells and epithelial cells at concentrations up to 10 μM[1][3]
BMS-378806 had CC50 values greater than 10 μM and 15 μM in MT-4 cells and human peripheral blood mononuclear cells, respectively[3] |
| References |
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| Additional Infomation |
BMS-378806 is a novel HIV-1 attachment inhibitor that specifically targets the viral envelope glycoprotein gp120[1]
BMS-378806 exerts its antiviral effect by binding to gp120, inducing conformational changes in gp120, and preventing gp120 from interacting with the host cell CD4 receptor, thereby blocking viral attachment and entry[2] BMS-378806 acts on the early stage of the HIV-1 life cycle (attachment/entry), which is different from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and integrase inhibitors that target the post-entry steps[3] BMS-378806 does not exhibit cross-resistance with existing antiretroviral drugs due to its unique targeting of the viral protein (gp120) and its mechanism of action[1] |
| Molecular Formula |
C22H22N4O4
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| Molecular Weight |
406.43
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| Exact Mass |
406.164
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| Elemental Analysis |
C, 65.01; H, 5.46; N, 13.78; O, 15.75
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| CAS # |
357263-13-9
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| Related CAS # |
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| PubChem CID |
5495818
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
622.3ºC at 760 mmHg
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| Flash Point |
330.2ºC
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| Index of Refraction |
1.647
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| LogP |
0.73
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
30
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| Complexity |
666
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| Defined Atom Stereocenter Count |
1
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| SMILES |
COC1=C2C(NC=C2C(C(N3CCN(C[C@H]3C)C(C4=CC=CC=C4)=O)=O)=O)=NC=C1
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| InChi Key |
FCBQJNCAKZSIAH-NDEPHWFRSA-N
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| InChi Code |
InChI=1S/C21H23FN2O3S/c22-17-3-1-15(2-4-17)13-16-7-9-24(10-8-16)11-12-28(26)18-5-6-19-20(14-18)27-21(25)23-19/h1-6,14,16H,7-13H2,(H,23,25)/t28-/m0/s1
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| Chemical Name |
4-benzoyl-1-((4-methoxy-1H- pyrrolo(2,3-b)pyridin-3-yl)oxoacetyl)-2- (R)-methylpiperazine
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| Synonyms |
BMS-378806; BMS 378806; BMS378806; BMS-806; BMS806; Bms 806.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : 50~81 mg/mL ( 123.02~199.29 mM )
Ethanol : ~81 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.15 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.15 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. View More
Solubility in Formulation 3: ≥ 1.67 mg/mL (4.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 30% PEG400+0.5% Tween 80+5% propylene glycol: 30mg/ml (73.81mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4604 mL | 12.3022 mL | 24.6045 mL | |
| 5 mM | 0.4921 mL | 2.4604 mL | 4.9209 mL | |
| 10 mM | 0.2460 mL | 1.2302 mL | 2.4604 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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