| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| Other Sizes |
| Targets |
pIC50: 7.3 (BCATm)[1]
Mitochondrial branched-chain aminotransferase (BCATm), also designated BCAT2. The enzyme catalyzes the reversible transamination of branched-chain amino acids (leucine, isoleucine, valine) to their respective branched-chain alpha-keto acids (BCKAs). BCAT-IN-1 is a selective inhibitor that targets the mitochondrial isoform over the cytosolic isoform (BCATc or BCAT1). |
|---|---|
| ln Vitro |
In human cells, BCAT-IN-1 (compound 8b) inhibits BCATm with a pIC50 of 7.0 [1]. In cell tests, BCAT-IN-1 inhibits mouse BCATm with a pIC50 of 5.9 [1].
BCAT-IN-1 is a potent inhibitor of human BCATm with a biochemical pIC50 of 7.3 (approximately 50 nM). It demonstrates approximately 100-fold selectivity for BCATm over the cytosolic isoform BCATc (pIC50=5.4). This high selectivity makes it a valuable tool for dissecting the distinct functions of the two BCAT isoforms. It is competitive with the substrate, binding to the active site. |
| ln Vivo |
In acute mouse models, BCAT-IN-1 (Compound 8b) (30–300 mg/kg; oral) raises c BCAA levels for an extended period of time [1]. Oral bioavailability (F=28%) and Cmax (1648 ng/mL) are demonstrated by BCAT-IN-1 (5 mg/kg; po) in mice [1]. BCAT-IN-1 (1 mg/kg; iv) half-life (t1/2=9.2 h) and clearance rate (Cl=4.0 mL/min/kg) in mice [1].
In vivo, BCAT-IN-1 has been used in animal models of metabolic disease. By inhibiting BCATm, it effectively reduces the catabolism of BCAAs, leading to an increase in circulating BCAA levels. This pharmacodynamic effect can be used to investigate the role of BCAA metabolism in conditions such as obesity, insulin resistance, and heart failure. The compound was identified to be orally active and in vivo efficacious. |
| Enzyme Assay |
A standard biochemical assay for BCATm uses a coupled enzyme system. The assay measures the production of branched-chain alpha-keto acid (BCKA), which is then reacted with a detection reagent. The reaction mix contains recombinant human BCATm, the substrate L-leucine, alpha-ketoglutarate, and the test inhibitor. The assay is initiated by adding the enzyme, and the production of BCKA is measured by absorbance (e.g., at 340 nm). The pIC50 is determined from the inhibition curve.
|
| Cell Assay |
A cellular activity assay for BCATm is difficult to perform in standard cell culture due to the presence of both BCAT isoforms and the abundance of BCAAs in media. To confirm cellular activity, one can treat cells (e.g., primary hepatocytes) with the compound and then measure the levels of BCAAs and BCKAs in the culture supernatant or cell lysates using LC-MS. An increase in BCAAs and a decrease in BCKAs indicates successful BCATm inhibition.
|
| Animal Protocol |
In vivo efficacy of BCAT-IN-1 can be assessed in a mouse model of metabolic disease, such as diet-induced obesity (DIO) or a genetic model of BCAA accumulation. Mice are dosed orally with the compound (or vehicle) daily for several weeks. Endpoints include measurement of plasma and tissue BCAA levels (by LC-MS), glucose tolerance tests (GTT), insulin tolerance tests (ITT), and other markers of metabolic health (e.g., body weight, fat mass).
|
| ADME/Pharmacokinetics |
BCAT-IN-1 is an orally active compound. This was a key design goal and has been demonstrated in animal studies where it was administered via oral gavage to achieve significant drug exposure and in vivo efficacy. The specific ADME (absorption, distribution, metabolism, excretion) parameters and half-life are not detailed in the referenced literature, but its oral bioavailability allows for convenient dosing in metabolic research.
|
| Toxicity/Toxicokinetics |
Specific toxicological data for BCAT-IN-1 is not available in standard research resources. As a potent metabolic enzyme inhibitor, its on-target toxicity would involve altering BCAA catabolism. This might lead to an accumulation of BCAAs, which in humans is associated with the rare disease maple syrup urine disease (MSUD) if not properly managed. However, at research doses, it has been used in vivo without reporting acute toxicity or animal welfare concerns.
|
| References |
[1]. Deng H, et, al. Discovery and Optimization of Potent, Selective, and in Vivo Efficacious 2-Aryl Benzimidazole BCATm Inhibitors. ACS Med Chem Lett. 2016 Feb 8;7(4):379-84.
|
| Additional Infomation |
BCAT-IN-1 was identified through a DNA-encoded library screening campaign followed by structure-based optimization. It belongs to the 2-aryl benzimidazole chemotype. This compound is a lead for the development of therapeutics for metabolic diseases associated with elevated BCAA levels, such as certain forms of insulin resistance and heart failure. It is not an approved drug and is strictly a research tool. The CAS number 1875078-61-7 is for the free base form, while the related product BCAT-IN-1 is the active inhibitor.
|
| Molecular Formula |
C25H24BRN5O2S
|
|---|---|
| Molecular Weight |
538.459362983704
|
| Exact Mass |
537.083
|
| CAS # |
1875078-61-7
|
| PubChem CID |
118988431
|
| Appearance |
White to off-white solid powder
|
| LogP |
4.6
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
34
|
| Complexity |
744
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
CNC(=O)C1=CC2=C(C=C1)N(C(=N2)C3=CC=CC=N3)[C@@H]4CCC[C@@H](C4)NC(=O)C5=CC=C(S5)Br
|
| InChi Key |
PGSKODUPOMCUEJ-DLBZAZTESA-N
|
| InChi Code |
InChI=1S/C25H24BrN5O2S/c1-27-24(32)15-8-9-20-19(13-15)30-23(18-7-2-3-12-28-18)31(20)17-6-4-5-16(14-17)29-25(33)21-10-11-22(26)34-21/h2-3,7-13,16-17H,4-6,14H2,1H3,(H,27,32)(H,29,33)/t16-,17+/m0/s1
|
| Chemical Name |
1-[(1R,3S)-3-[(5-bromothiophene-2-carbonyl)amino]cyclohexyl]-N-methyl-2-pyridin-2-ylbenzimidazole-5-carboxamide
|
| 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) |
DMSO: 100 mg/mL (185.71 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.64 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 (4.64 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 | 1.8571 mL | 9.2857 mL | 18.5715 mL | |
| 5 mM | 0.3714 mL | 1.8571 mL | 3.7143 mL | |
| 10 mM | 0.1857 mL | 0.9286 mL | 1.8571 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
