| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg |
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| 10mg | |||
| Other Sizes |
| Targets |
Monoacylglycerol acyltransferase 2 (MGAT2)
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|---|---|
| ln Vitro |
In vitro assays demonstrate that BMS-963272 potently inhibits human MGAT2 with an IC50 of 7.1 nM. The compound exhibits good metabolic stability, with 100% remaining in both human and mouse liver microsomes after 10 minutes of incubation. Cellular activity is confirmed using MGAT2-overexpressing cell lines, where it inhibits triglyceride synthesis in a dose-dependent manner. No cytotoxicity is observed at relevant concentrations.
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| ln Vivo |
Treatment with BMS-963272 decreases inflammation and fibrosis in the CDAHFD and STAM murine NASH models. On-target weight loss efficacy is demonstrated in diet-induced obese mouse models. The compound has an acceptable safety and tolerability profile in multiple preclinical species. Phase 1 studies in healthy human adults with obesity show acceptable safety and tolerability at daily doses up to 300 mg once daily orally.
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| Enzyme Assay |
Recombinant human MGAT2 is expressed in insect cells (Sf9) and microsomal fractions are isolated. The enzyme activity assay uses 1-monoolein (1-monoacylglycerol) and [14C]-oleoyl-CoA as substrates in a reaction buffer containing Tris-HCl, MgCl2, and BSA. Reactions are incubated at room temperature for 30-60 minutes, stopped by organic extraction, and the product (triglyceride) is separated by TLC and quantified by scintillation counting. IC50 values are derived from dose-response curves.
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| Cell Assay |
MGAT2-overexpressing HEK293 cells are cultured in DMEM with 10% FBS and selection antibiotics. Cells are treated with BMS-963272 (0.1-1000 nM) for 4-24 hours in serum-free medium containing BSA-complexed oleic acid. Cellular triglyceride content is quantified using enzymatic colorimetric kits after lipid extraction. Alternatively, incorporation of [14C]-oleic acid into triglycerides is measured. Cell viability is assessed by CellTiter-Glo or MTT assays.
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| Animal Protocol |
For in vivo efficacy, male C57BL/6J mice are fed a CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or placed on a high-fat diet (60% kcal from fat) for 8-16 weeks to induce NASH and obesity. BMS-963272 is formulated in a suitable vehicle (e.g., 0.5% methylcellulose) and administered orally once or twice daily at doses ranging from 1-30 mg/kg for 4-12 weeks. Endpoints include body weight, food intake, plasma triglycerides, liver histology (steatosis, inflammation, fibrosis by H&E and Sirius Red), liver triglycerides, plasma ALT/AST, and hepatic gene expression.
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| ADME/Pharmacokinetics |
BMS-963272 is orally bioavailable with acceptable pharmacokinetic properties across preclinical species. Detailed parameters are available in the literature: it exhibits moderate to high oral bioavailability (e.g., ~50-80% in rodents), a plasma half-life of 2-6 hours, and low to moderate plasma protein binding. It is metabolized primarily by CYP3A4, with a clean drug-drug interaction profile.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies in multiple species (rat, dog) have established an acceptable safety margin for BMS-963272. No significant genotoxicity, cardiotoxicity (hERG, in vivo QT studies), or organ toxicity is observed at therapeutic doses. The no-observed-adverse-effect level (NOAEL) is determined in 28-day and 90-day toxicology studies, supporting clinical development.
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| References | |
| Additional Infomation |
BMS-963272 advanced into Phase 1 clinical trials for metabolic disorders. It is a clinical candidate for obesity and NASH. The compound was discovered via high-throughput screening of a BMS internal compound collection. Phase 1 studies in healthy adults with obesity showed acceptable safety, tolerability, and pharmacokinetics. This compound is not yet approved for clinical use; development status may have changed. The CAS number is 1441057-15-3.
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| Molecular Formula |
C24H21F6N5O2
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|---|---|
| Molecular Weight |
525.446265935898
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| Exact Mass |
525.159
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| CAS # |
1441057-15-3
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| PubChem CID |
71582672
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
5.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
37
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| Complexity |
835
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1(=O)N[C@@](C2=CC=C(OCCCC(F)(F)F)C=C2)(C(F)(F)F)CC(C2=CC=C(C)C=C2)=C1C1=NNN=N1
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| InChi Key |
AEMPUAWUDAMJBV-QFIPXVFZSA-N
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| InChi Code |
InChI=1S/C24H21F6N5O2/c1-14-3-5-15(6-4-14)18-13-22(24(28,29)30,31-21(36)19(18)20-32-34-35-33-20)16-7-9-17(10-8-16)37-12-2-11-23(25,26)27/h3-10H,2,11-13H2,1H3,(H,31,36)(H,32,33,34,35)/t22-/m0/s1
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| Chemical Name |
(2S)-4-(4-methylphenyl)-5-(2H-tetrazol-5-yl)-2-[4-(4,4,4-trifluorobutoxy)phenyl]-2-(trifluoromethyl)-1,3-dihydropyridin-6-one
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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 |
| 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: 250 mg/mL (475.78 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.96 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 20.8 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: ≥ 2.08 mg/mL (3.96 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 20.8 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 | 1.9031 mL | 9.5157 mL | 19.0313 mL | |
| 5 mM | 0.3806 mL | 1.9031 mL | 3.8063 mL | |
| 10 mM | 0.1903 mL | 0.9516 mL | 1.9031 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04766476
Conditions:Nonalcoholic Fatty Liver DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT04116632
Conditions:Obese But Otherwise Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT04124003
Conditions:Healthy Participants
Title:Randomized, Placebo-Controlled, Double-Blind, Ascending Single and Multiple Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BMS-963272 in Healthy Subjects
Status:Completed
updateDate:2015-07-22
Ctid:NCT02327273
Link: https://clinicaltrials.gov/ct2/show/NCT02327273
Conditions:HealthyProducts are for research use only; We do not sell to patients
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