BDM44768
BDM44768 is an insulin-degrading enzyme (IDE) inhibitor (human IC50 = 0.06 μM; Ki = 60 nM). BDM44768 impairs D-Glucose (HY-B0389) tolerance, enhances Insulin (HY-P0035) signaling, and increases Amyloid-β concentration in an IDE-dependent manner by chelating the catalytic zinc, stabilizing the closed conformation, and binding the substrate/catalytic cleft. BDM44768 can be used in research on diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD).
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- CAS 番号: 2011754-00-8
- 分子式: C24H22FN5O3
- 分子量:447.46
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保管条件:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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生物活性
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化学情報
- プロトコル
- 純度とドキュメンテーション
- 参考文献
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Help & FAQs
生物活性
製品説明
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hIDE 0.06 μM (IC50) |
IDE 60 nM (Ki) |
体外実験
BDM44768 (15 μM; overnight for mRNA detection, 24 h for protein detection) enhances TN- or palmitate-induced IRE1 pathway activation in HepG2 cells, increasing XBP1s, ERDJ4, and p-IRE1α, while alone it does not activate the UPR[4].
BDM44768 (1.25 μM; 30 min) reversibly inhibits hIDE, and activity is restored after 100-fold dilution[6].
BDM44768 (30 mM; 2 h) binds to IDE in HepG2 cells with a ΔT_agg of 6.4 °C and a cell/medium ratio of 0.11[6].
BDM44768 (1-10 µM; 1 h) shows good Caco-2 cell membrane permeability at 1 and 10 µM[1].
BDM44768 (6.25-50 mM) binds hIDE in solution, and its interaction is stronger than that of the 1,5 isomer[1].
BDM44768 (20 mM) induces the transition of hIDE from an open conformation to a closed conformation in solution[1].
BDM44768 (200 mM) binds the hIDE catalytic site and locks hIDE in a closed inhibitory conformation[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Differentiated human SH-SY5Y neuroblastoma cells
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Concentration:10 mM; 30 mM
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Incubation Time:48 h
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Result:Revealed significantly increased concentrations of Aβ1-40 in culture supernatants of cells incubated with BDM44768, but not with 10, a 100-fold less active analogue.
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Cell Line:HepG2 human hepatocellular carcinoma cells
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Concentration:15 μM
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Incubation Time:overnight (mRNA); 24 h (protein)
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Result:Had no impact on UPR markers in unstressed cells.
Potentiated the effect of TN on the IRE1α pathway, specifically XBP1s, and phosphorylated and total IRE1α proteins.
The combination of BDM44768 with palmitate potentiated expression of IRE1 pathway-related genes XBP1s and ERDJ4 and increased phosphorylated IRE1α protein.
Failed to increase XBP1s and Erdj4 expression in IDE-silenced HepG2 cells stressed with TN.
Other UPR-related pathways were not impacted.
Parmacokinetics
| Species | Dose | Route | Cmax | Tmax | T1/2 |
|---|---|---|---|---|---|
| Mice[1] | 30 mg/kg | i.p. | 9.2 μM | 10 min | 80 min |
体内実験
BDM44768 (50 mg/kg; intraperitoneal injection; single administration; 15 min before oral glucose) does not impair glucose tolerance in C57BL/6J IDE−/− mice, indicating that this glucose intolerance effect depends on IDE[1].
BDM44768 (50 mg/kg; intraperitoneal injection; single administration; 15 min before oral glucose) acutely impairs glucose tolerance and increases insulinemia in NOD wild-type mice[1].
BDM44768 (50 mg/kg; intraperitoneal injection; single administration; 15 min before oral glucose) does not impair glucose tolerance in NOD IDE−/− mice, consistent with an IDE-dependent effect[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6J wild-type (male 12-week-old for ITT and PTT; male or female 11-16-week-old for OGTT/IPGTT)[1]
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Dosage:50 mg/kg
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Administration:i.p.; single administration; 15 min before challenge
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Result:In the ITT, BDM44768 slightly increased serum insulin concentrations, with an effect at 30 min, and increased phosphorylation of liver and muscle insulin receptor, Akt, and ERK; it tended to enhance the glucose-lowering effect of insulin at 30 and 60 min.
In the OGTT, BDM44768 increased plasma glucose concentrations from 15 to 90 min after oral glucose load, and the AUC of glycaemia as a function of time was increased; plasma insulin levels at baseline, 15, and 90 min after glucose load were similar to vehicle.
In the IPGTT, BDM44768 increased plasma glucose concentrations at all time points after i.p. glucose.
In the PTT, glucose excursion curves and AUC were similar to vehicle.
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Animal Model:C57BL/6J IDE−/− (male or female, 11-16 weeks)[1]
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Dosage:50 mg/kg
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Administration:i.p.; single administration; 15 min before oral glucose
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Result:did not induce glucose intolerance in IDE−/− mice; plasma insulin concentrations were not changed by BDM44768 in these mice.
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Animal Model:NOD wild-type (female, 14 weeks)[1]
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Dosage:50 mg/kg
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Administration:i.p.; single administration; 15 min before oral glucose
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Result:produced a strong impairment of glucose tolerance in WT NOD mice.
Plasma insulin levels were elevated at 15, 90, and 180 min compared with WT; the hyperinsulinemia induced by BDM44768 in WT NOD mice was similar to the hyperinsulinemia in IDE−/− NOD mice given vehicle or BDM44768.
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Animal Model:NOD IDE−/− (female, 14 weeks)[1]
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Dosage:50 mg/kg
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Administration:i.p.; single administration; 15 min before oral glucose
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Result:did not induce glucose intolerance in NOD IDE−/− mice.
Plasma insulin in NOD IDE−/− mice given BDM44768 was comparable to NOD IDE−/− mice given vehicle and to WT NOD mice given BDM44768.
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Animal Model:C57BL/6J (wild-type, 20-week-old)[4]
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Dosage:50 mg/kg
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Administration:i.p.; two administrations; 8 h and 2 h before sacrifice
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Result:In tunicamycin-injected mice, BDM44768 significantly potentiated TN-induced hepatic Xbp1s and Erdj4 mRNA expression and increased hepatic IRE1α phosphorylation.
Also stimulated PERK-related genes (Atf4, Gadd34, and Chop) in TN + BDM44768-treated mice compared with TN-injected mice.
Mice treated with TN + BDM44768 showed further increased hepatic triglyceride accumulation, higher neutral lipid staining by Oil Red O, and an increased number of lipid droplets by electron microscopy compared with TN-injected mice.
Consistently, BDM44768 in acute ER stress conditions increased the expression of FA import (Cd36), LD formation (Adrp, Fitm1) and LD fusion (Fsp27) genes compared with TN-stimulated mice.
In TN-treated mice, BDM44768 increased hormone-sensitive lipase (HsL) phosphorylation in adipose tissue.
CD36 protein was higher in the liver from BDM44768 + TN-treated compared with TN alone-treated mice.
化学情報
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CAS 番号 2011754-00-8
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分子量 447.46
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分子式 C24H22FN5O3
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SMILES
ONC(C[C@H](N1C=C(N=N1)CNC(C2=CC=C(C=C2)F)=O)CC3=CC4=C(C=CC=C4)C=C3)=O
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輸送条件
Room temperature in continental US; may vary elsewhere.
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保管条件
Please store the product under the recommended conditions in the Certificate of Analysis.
純度とドキュメンテーション
参考文献
[1]. Deprez-Poulain R, et al. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice. Nature communications. 2015 Sep 23;6:8250. [Content Brief]
[4]. Andres M, et al. Insulin-degrading enzyme inhibition increases the unfolded protein response and favours lipid accumulation in the liver. British journal of pharmacology. 2024 Oct;181(19):3610-3626. [Content Brief]
Calculators
濃度 (開始) × 体積 (開始) = 濃度 (終了) × 体積 (終了)
BDM44768 関連分類
HY-114611 関連分類
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