| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Brexpiprazole S-oxide (DM-3411) is the S-oxidized, CYP3A4-mediated and major metabolite of Brexpiprazole (Rexulti; OPC34712; OPC-34712), which is an approved atypical antipsychotic medication and a partial agonist of human 5-HT1A as well as dopamine receptor with Kis of 0.12 nM and 0.3 nM, respectively. Brexpiprazole is also a 5-HT2A receptor antagonist with a Ki of 0.47 nM.
| Targets |
5-HT1A Receptor (Ki = 0.12 nM); 5-HT2A Receptor (Ki = 0.47 nM); D2 Receptor (Ki = 0.3 nM)
|
|---|---|
| ln Vitro |
As a new atypical antipsychotic, brexpiprazole is primarily metabolized by cytochrome P450 3A4 (CYP3A4). However, genetic polymorphisms in CYP3A4 cause wide variability in individuals' responses to brexpiprazole, leading to unpredictable adverse side effects or even therapeutic failure. The present study was designed to systematically study the effects of 26 recombinant CYP3A4 variants on the metabolism of brexpiprazole and investigate their enzymatic activity. Wild-type CYP3A4 and the 26 variants were incubated with the substrate brexpiprazole for 30 min at 37 °C. The metabolite DM-3411 was detected using ultraperformance liquid chromatography-tandem mass spectrometry. The activity of the wild-type CYP3A4 and 26 of its variants was analyzed. Then, the mechanism underlying the changes in enzyme function was observed using molecular dynamics simulations and molecular docking. Compared with CYP3A4.1, the enzymatic activities of CYP3A4.19, -.24, and -.28 were not significantly different (from 91.82% to 96.25%), but CYP3A4.14 and CYP3A4.15 exhibited higher enzyme activity (from 117.9 to 127.5%). The remaining 21 isoforms, including CYP3A4.2, -.3, -.4, -.5, -.7, -.8, -.9, -.10, -.11, -.12, -.13, -.16, -.17, -.18, -.20, -.23, -.29, -.31, -.32, -.33 and -.34, displayed lower enzymatic activities (from 2.90% to 75.72%). The results obtained from computer modeling indicated that weak binding affinity impaired the function of CYP3A4.32. Mutations that occur around the active site might lead to a loss of enzymatic activity, while the variants located far away from the active site perhaps had little effect on function of CYP3A4. These comprehensive data provide a reference and prediction for treatment strategies and risk assessments of brexpiprazole [1].
|
| References |
|
| Additional Infomation |
Brexpiprazole, a novel atypical antipsychotic drug, is currently being tested in clinical trials for treatment of psychiatric disorders, such as schizophrenia and major depressive disorder. The drug is known to act through a combination of partial agonistic activity at 5-hydroxytryptamine (5-HT)1A, and dopamine D2 receptors, and antagonistic activity at 5-HT2A receptors. Accumulating evidence suggests that antipsychotic drugs act by promoting neurite outgrowth. In this study, we examined whether brexpiprazole affected neurite outgrowth in cell culture. We found that brexpiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. The selective 5-HT1A receptor antagonist, WAY-100,635, was able to block the effects of brexpiprazole on neurite outgrowth, unlike the selective dopamine D2 receptor antagonist, raclopride. Furthermore, the selective 5-HT2A receptor antagonist M100907, but not DOI (5-HT2A receptor agonist), significantly potentiated NGF-induced neurite outgrowth. Moreover, xestospongin C and 2-aminoethoxydiphenyl borate (2-APB), both specific inhibitors of inositol 1,4,5-triphosphate (IP3) receptors, significantly blocked the effects of brexpiprazole. These findings suggest that brexpiprazole-induced neurite outgrowth is mediated through 5-HT1A and 5-HT2A receptors, and subsequent Ca(2+) signaling via IP3 receptors.[2]
|
| Molecular Formula |
C₂₅H₂₇N₃O₃S
|
|---|---|
| Molecular Weight |
449.57
|
| Exact Mass |
449.177
|
| CAS # |
1191900-51-2
|
| Related CAS # |
Brexpiprazole S-oxide-d8;2748605-29-8
|
| PubChem CID |
44256485
|
| Appearance |
Typically exists as Off-white to light yellow solid at room temperature
|
| Density |
1.4±0.1 g/cm3
|
| Index of Refraction |
1.693
|
| LogP |
3.1
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
32
|
| Complexity |
749
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
S1(C=CC2=C1C=CC=C2N1CCN(CCCCOC2=CC=C3C=CC(NC3=C2)=O)CC1)=O
|
| InChi Key |
VJYXYAVCCLPIPM-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C25H27N3O3S/c29-25-9-7-19-6-8-20(18-22(19)26-25)31-16-2-1-11-27-12-14-28(15-13-27)23-4-3-5-24-21(23)10-17-32(24)30/h3-10,17-18H,1-2,11-16H2,(H,26,29)
|
| Chemical Name |
7-[4-[4-(1-oxo-1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one
|
| Synonyms |
DM-3411; DM3411; Brexpiprazole S-oxide; 1191900-51-2; DM-3411; 2(1H)-Quinolinone, 7-(4-(4-(1-oxidobenzo(b)thien-4-yl)-1-piperazinyl)butoxy)-; BrexpiprazoleS-Oxide; N22UPQ09R0; UNII-N22UPQ09R0; 7-[4-[4-(1-oxo-1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one; DM 3411
|
| 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 : ~25 mg/mL (~55.61 mM)
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2243 mL | 11.1217 mL | 22.2435 mL | |
| 5 mM | 0.4449 mL | 2.2243 mL | 4.4487 mL | |
| 10 mM | 0.2224 mL | 1.1122 mL | 2.2243 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
