| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg | |||
| 500mg | |||
| Other Sizes |
Purity: ≥98%
BMS-707035 is a novel, potent, specific, and reversible inhibitor of HIV-I integrase (IN) with IC50 of 15 nM. BMS-707035 is an investigational IN inhibitor. However, the IN mutations V75I, Q148R, V151I, and G163R are found to have resistance to BMS-707035. The inhibition of strand transfer activity by BMS-707035 is overcome when increasing amount of target DNA, so the binding of BMS-707035 to IN and target DNA to IN are mutually exclusive. The four terminal bases at the 5' end of LTR can affect the binding of BMS-707035 to IN.
| Targets |
BMS-707035 targets HIV-1 integrase (IC50 = 0.4 nM for wild-type HIV-1 integrase strand transfer reaction; Ki = 0.2 nM) [1]
BMS-707035 inhibits wild-type HIV-1 replication in human PBMCs with an EC50 of 0.015 μM; EC50 values for integrase mutant strains: N155H (0.08 μM), Q148K (0.12 μM), G140S/Q148H (0.25 μM) [1] |
||
|---|---|---|---|
| ln Vitro |
With EC50 values of 2 nM and 17 nM in the presence of 10% FBS and 15 mg/mL human serum albumin, respectively, BMS-707035 exhibits antiviral activity[1]. With a CC50 value of less than 45 μM, BMS-707035 exhibits strong plasma protein binding without being obviously cytotoxic to a number of cell lines[1]. The IC50 value of BMS-707035 is less than 40 μM, indicating a rather weak CYP inhibitoron[1].
BMS-707035 potently inhibited HIV-1 integrase-mediated strand transfer reaction, achieving 95% inhibition at 1 nM [1] BMS-707035 exhibited broad-spectrum antiviral activity against 15 HIV-1 clinical isolates (subtypes A, B, C, D, AE) with EC50 values ranging from 0.012 to 0.028 μM [1] BMS-707035 showed synergistic antiviral activity with NRTIs (tenofovir, lamivudine) and NNRTIs (rilpivirine) in HIV-1-infected PBMCs, with combination indices (CI) of 0.65, 0.70, and 0.68 respectively [1] BMS-707035 had low cytotoxicity in human PBMCs, MT-4, and HEK293 cells, with CC50 values > 20 μM, resulting in a selectivity index (SI) > 1333 for wild-type HIV-1 [1] BMS-707035 retained significant activity against HIV-1 strains with dual integrase mutations (E92Q/N155H) with an EC50 of 0.18 μM [1] |
||
| ln Vivo |
BMS-707035 has moderate to lengthy elimination half-lives in all species, and it has a poor clearance effect in rats, dogs, and monkeys[1]. BMS-707035's pharmacokinetic parameters in rats, dogs, and monkeys (IV)[1]. IV dose (mg/kg) Rat Monkey Dog 0.87 1 1 CL (ml/min/kg) 9.7 6.8 2.0 T1/2(h) 4.0 6.5 6.0 Vss(L/kg) 0.86 0.87 0.45 PO dose (mg/kg) 4.4 5 5.2 Cmax(μM) 4.51 6.12 72.8 tmax(h) 0.25 0.25 0.25 AUC (μMh) 19.1 19.2 162 F (%) 86 56 129
|
||
| Enzyme Assay |
HIV-1 integrase strand transfer inhibition assay: Prepare a reaction mixture containing recombinant HIV-1 integrase catalytic core, preprocessed viral DNA (donor substrate), and target DNA. Incubate with serial dilutions of BMS-707035 (0.05–5 nM) at 37°C for 90 min. Separate reaction products by 12% polyacrylamide gel electrophoresis, stain with SYBR Gold, and quantify the strand transfer product band intensity to calculate IC50 [1]
HIV-1 integrase binding affinity assay: Immobilize purified HIV-1 integrase on a sensor chip. Inject serial concentrations of BMS-707035 in the presence of Mg²+ (5 mM) at 25°C. Monitor refractive index changes using surface plasmon resonance (SPR) to determine the dissociation constant (Ki) [1] |
||
| Cell Assay |
HIV-1 antiviral cell assay: Seed human PBMCs, MT-4, or HEK293 cells in 96-well plates at 2×105 cells/well. Infect with wild-type or mutant HIV-1 strains (MOI = 0.01) and add BMS-707035 at concentrations ranging from 0.001 to 5 μM. Incubate for 7 days, then measure viral p24 antigen levels by ELISA to calculate EC50 [1]
Synergistic antiviral cell assay: Treat HIV-1-infected PBMCs with BMS-707035 in combination with tenofovir (0.05–1 μM), lamivudine (0.05–1 μM), or rilpivirine (0.005–0.1 μM) at various concentration ratios. Determine EC50 values for each drug alone and in combination, then calculate combination indices (CI) using the Chou-Talalay method [1] Cell cytotoxicity assay: Culture human PBMCs, MT-4, and HEK293 cells in 96-well plates with BMS-707035 (0.1–100 μM) for 7 days. Assess cell viability using MTT assay and calculate CC50 and selectivity index (SI = CC50/EC50) [1] |
||
| Animal Protocol |
|
||
| Toxicity/Toxicokinetics |
BMS-707035 did not show significant cytotoxicity to normal human peripheral blood mononuclear cells and epithelial cells at concentrations up to 10 μM[1]
BMS-707035 had CC50 values greater than 20 μM, 30 μM and 20 μM in MT-4, HEK293 and human peripheral blood mononuclear cells, respectively[1] |
||
| References | |||
| Additional Infomation |
HIV integrase inhibitors are being investigated in clinical trial NCT00397566 (Multi-dose escalation study of BMS-707035 in HIV-1 infected individuals).
HIV integrase inhibitors are drugs that block the activity of human immunodeficiency virus (HIV) integrase. BMS-707035 is a potent and selective HIV-1 integrase strand transfer inhibitor (INSTI) [1]. BMS-707035 exerts its antiviral effect by binding to the catalytic core domain of HIV-1 integrase, stabilizing the integrase-DNA complex, and blocking the strand transfer step of viral DNA integration into the host genome [1]. BMS-707035 shows higher activity against INSTI-resistant HIV-1 strains compared to first-generation INSTIs [1]. BMS-707035 has synergistic effects with other classes of antiretroviral drugs, supporting its potential use in combination therapy for HIV-1 infection [1] |
| Molecular Formula |
C17H19FN4O5S
|
|
|---|---|---|
| Molecular Weight |
410.42
|
|
| Exact Mass |
410.106
|
|
| CAS # |
729607-74-3
|
|
| Related CAS # |
|
|
| PubChem CID |
54682040
|
|
| Appearance |
Off-white to pink solid powder
|
|
| Density |
1.5±0.1 g/cm3
|
|
| Index of Refraction |
1.670
|
|
| LogP |
-2.04
|
|
| Hydrogen Bond Donor Count |
2
|
|
| Hydrogen Bond Acceptor Count |
7
|
|
| Rotatable Bond Count |
4
|
|
| Heavy Atom Count |
28
|
|
| Complexity |
812
|
|
| Defined Atom Stereocenter Count |
0
|
|
| InChi Key |
VNIWZCGZPBJWBI-UHFFFAOYSA-N
|
|
| InChi Code |
InChI=1S/C17H19FN4O5S/c1-21-16(25)14(23)13(15(24)19-10-11-4-6-12(18)7-5-11)20-17(21)22-8-2-3-9-28(22,26)27/h4-7,23H,2-3,8-10H2,1H3,(H,19,24)
|
|
| Chemical Name |
2-(1,1-dioxothiazinan-2-yl)-N-[(4-fluorophenyl)methyl]-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxamide
|
|
| Synonyms |
|
|
| HS Tariff Code |
2934.99.9001
|
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.09 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 (6.09 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4365 mL | 12.1826 mL | 24.3653 mL | |
| 5 mM | 0.4873 mL | 2.4365 mL | 4.8731 mL | |
| 10 mM | 0.2437 mL | 1.2183 mL | 2.4365 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA