BMS-378806

Catalog No.S2632 Batch:S263201

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Technical Data

Formula

C22H22N4O4
Molecular Weight 406.43 CAS No. 357263-13-9
Solubility (25°C)* In vitro DMSO 81 mg/mL (199.29 mM)
Ethanol 3 mg/mL (7.38 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description BMS-378806 (BMS 806) selectively inhibits the binding of HIV-1 gp120 to the CD4 receptor with EC50 of 0.85-26.5 nM in virus.
Targets
CD4-gp120 interactions [1]
0.85 nM-26.5 nM(EC50)
In 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. [1] 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. [2]
In 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. [1] 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). [3]

Protocol (from reference)

Kinase Assay:[1]
  • Drug susceptibility 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 Dunnett's test. These comparisons are made separately within each assay system. Dunnett's 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 Fieller's 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.

Cell Assay:[1]
  • Cell lines

    MT-2 cells

  • Concentrations

    0-3 mM

  • Incubation Time

    6 days

  • Method

    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).

Animal Study:[1]
  • Animal Models

    Rat, dog and monkey

  • Dosages

    5 mg/kg, 3.4 mg/kg and 3.4 mg/kg.

  • Administration

    BMS-806 is intravenously administered.

Selleck's BMS-378806 has been cited by 5 publications

Asymmetric conformations of cleaved HIV-1 envelope glycoprotein trimers in styrene-maleic acid lipid nanoparticles [ Commun Biol, 2023, 6(1):535] PubMed: 37202420
Asymmetric Structures and Conformational Plasticity of the Uncleaved Full-Length Human Immunodeficiency Virus Envelope Glycoprotein Trimer [ J Virol, 2021, 95(24):e0052921] PubMed: 34549974
Long-Acting BMS-378806 Analogues Stabilize the State-1 Conformation of the Human Immunodeficiency Virus (HIV-1) Envelope Glycoproteins. [ J Virol, 2020, 10.1128/JVI.00148-20] PubMed: 32161177
HIV infection is influenced by dynamin at 3 independent points in the viral life cycle [ Traffic, 2017, 18(6):392-410] PubMed: 28321960
CD4-induced activation in a soluble HIV-1 Env trimer [ Structure, 2014, 22(7):974-84] PubMed: 24931470

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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