Art. -Nr.: HY-114611

BDM44768

BDM44768 is an insulin-degrading enzyme (IDE) inhibitor (human IC₅₀ = 0.06 μM; K_i = 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. Nr.: 2011754-00-8
Formel: C₂₄H₂₂FN₅O₃
Molecular Weight:447.46

Speicherung:

Please store the product under the recommended conditions in the Certificate of Analysis.

Data Sheet (288 KB)

BDM44768 Chemical Structure

CAS. Nr.: 2011754-00-8

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Use of MCE Products

Strong Fluorescence Signal / Multi-Disciplinary Applications / High Fluorescence Specificity

Biologische Aktivität
- Beschreibung
- IC₅₀ & Target
- In Vitro
- Parmacokinetics
- In Vivo
Chemical Information
Reinheit & Dokumentation
Verweise
Calculators
Help & FAQs
Classifications
Bioz

Biologische Aktivität

Beschreibung

IC₅₀ & Target

^[1]^[3]

hIDE

0.06 μM (IC₅₀)

IDE

60 nM (Ki)

In Vitro

Aβ/Tau/α-Synuclein AggregationCarbohydrate MetabolismProtein/Amino Acid MetabolismEndoplasmic Reticulum StressLipid MetabolismOthers

Aβ/Tau/α-Synuclein Aggregation

BDM44768 (10-30 mM; 48 h) inhibits IDE in SH-SY5Y cells and dose-dependently increases secreted Aβ1-40^[1].

Carbohydrate Metabolism

BDM44768 (1 h) protects secreted insulin from degradation in isolated mouse islets without affecting glucose-stimulated insulin secretion^[1].

Carbohydrate Metabolism

Protein/Amino Acid Metabolism

BDM44768 inhibits IDE with a K_i of approximately 60 nM for insulin and stabilizes IDE in a closed conformation^[3].

Endoplasmic Reticulum Stress

BDM44768 (30 μM; 2 h) binds to IDE in HepG2 cells and increases T_Agg by 5°C under control, TN-induced, and Palmitic acid (HY-N0830)-induced ER stress conditions^[4].
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].

Endoplasmic Reticulum Stress

Lipid Metabolism

BDM44768 (15 μM) increases lipid droplet accumulation in palmitate-stimulated HepG2 cells through an IRE1-dependent mechanism^[4].

Protein/Amino Acid Metabolism

BDM44768 inhibits wild-type hIDE with an IC₅₀ of 0.30 μM using the ATTO 655 peptide substrate and 0.056 μM using insulin, and inhibits cysteine-free hIDE with an IC₅₀ of 0.33 μM^[6].
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].

Protein/Amino Acid Metabolism

Aβ/Tau/α-Synuclein Aggregation

BDM44768 (compound 1) (10 min) inhibits human IDE with an IC₅₀ of 0.06 µM against native insulin and is the most active compound in the Aβ16-23-based hIDE assay^[1].

Others

BDM44768 (1-10 mM; 2 h-24 h) has favorable in vitro properties, including aqueous solubility of 58.0 µM, plasma stability, and microsomal stability^[1].
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.

ELISA Assay^[1]

Cell Line:

Differentiated human SH-SY5Y neuroblastoma cells
Concentration:

10 mM; 30 mM
Incubation Time:

48 h
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.

Real Time qPCR^[4]

Cell Line:

HepG2 human hepatocellular carcinoma cells
Concentration:

15 μM
Incubation Time:

overnight (mRNA); 24 h (protein)
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	C_max	T_max	T_1/2
Mice^[1]	30 mg/kg	i.p.	9.2 μM	10 min	80 min

In Vivo

Carbohydrate MetabolismEndoplasmic Reticulum StressLipid Metabolism

Carbohydrate Metabolism

BDM44768 (compound 1) (50 mg/kg; intraperitoneal injection; single administration; 15 min before challenge) acutely impairs glucose tolerance while enhancing insulin signaling in wild-type C57BL/6J mice^[1].
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].

Endoplasmic Reticulum Stress

Lipid Metabolism

BDM44768 (50 mg/kg; intraperitoneal injection; administered twice; 8 h and 2 h before sacrifice) enhances hepatic IRE1 pathway activation and aggravates hepatic lipid accumulation, increasing Trilaurin (HY-126573), lipid droplets, CD36, and adipose tissue HsL phosphorylation in Tunicamycin (HY-A0098)-induced acute ER stress in C57BL/6J wild-type mice^[4].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

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]
Dosage:

50 mg/kg
Administration:

i.p.; single administration; 15 min before challenge
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.

Animal Model:

C57BL/6J IDE^−/− (male or female, 11-16 weeks)^[1]
Dosage:

50 mg/kg
Administration:

i.p.; single administration; 15 min before oral glucose
Result:

did not induce glucose intolerance in IDE^−/− mice; plasma insulin concentrations were not changed by BDM44768 in these mice.

Animal Model:

NOD wild-type (female, 14 weeks)^[1]
Dosage:

50 mg/kg
Administration:

i.p.; single administration; 15 min before oral glucose
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.

Animal Model:

NOD IDE^−/− (female, 14 weeks)^[1]
Dosage:

50 mg/kg
Administration:

i.p.; single administration; 15 min before oral glucose
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.

Animal Model:

C57BL/6J (wild-type, 20-week-old)^[4]
Dosage:

50 mg/kg
Administration:

i.p.; two administrations; 8 h and 2 h before sacrifice
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.

Related Protocols :

Chemical Information

CAS. Nr. 2011754-00-8
Molecular Weight 447.46
Formel C₂₄H₂₂FN₅O₃
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
Versand

Room temperature in continental US; may vary elsewhere.
Speicherung

Please store the product under the recommended conditions in the Certificate of Analysis.

Reinheit & Dokumentation

Select Batch:

Reinheit: 99.98%

Assay: 99.98%

ee.: 99.98%

Data Sheet (288 KB)
COA (2659 KB)
Elemental Analysis Report (2659 KB)
HNMR (2659 KB)
CNMR (2659 KB)
RP-HPLC (2659 KB)
NP-HPLC (2659 KB)
MS (2659 KB)
LCMS (2659 KB)
IR (2659 KB)
GC (2659 KB)
OR (2659 KB)
SDS-PAGE (2659 KB)
SEC-HPLC (2659 KB)
Other Report (2659 KB)
Handling Instructions (2659 KB)

Verweise

[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]

[2]. González-Casimiro CM, et al. Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme. Biomedicines. 2021 Jan 17;9(1):86.

[3]. Leissring MA, et al. Targeting Insulin-Degrading Enzyme in Insulin Clearance. International journal of molecular sciences. 2021 Feb 24;22(5):2235.

[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]

[5]. Parvatkar PT, et al. Biocompatible reactions: Advances in kinetic target-guided synthesis. Trends in Chemistry. 2023 Sep 1;5(9):657-71.

[6]. Leroux F, et al. Identification of ebselen as a potent inhibitor of insulin degrading enzyme by a drug repurposing screening. European journal of medicinal chemistry. 2019 Oct 01;179:557-566.

Calculators

Molaritätsrechner

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

Mass Mass

Konzentration Konzentration

Volumen Volumen

Molecular Weight Molecular Weight

Verdünnungsrechner

Konzentration _{(Stammlösung)} × Volumen _{(Stammlösung)} = Konzentration _{(Ziellösung)} × Volumen _{(Ziellösung)}

Konzentration _{(Stammlösung)} Konzentration _{(Stammlösung)}

Volumen _{(Stammlösung)} Volumen _{(Stammlösung)}

Konzentration _{(Ziellösung)} Konzentration _{(Ziellösung)}

Volumen _{(Ziellösung)} Volumen _{(Ziellösung)}

Help & FAQs

How should lyophilized recombinant proteins be reconstituted and stored?

1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

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BDM44768