AD-9308
AD-9308 is an orally active, highly selective aldehyde dehydrogenase 2 (ALDH2) activator. AD-9308 alleviates oxidative stress, improves mitochondrial function, restores cell viability, reduces renal tubular injury, fibrosis and inflammatory responses, reverses ventricular remodeling, restores the activities of Dicer and superoxide dismutase, inhibits the IL-6 signaling pathway, reduces the accumulation of 4-HNE-protein adducts, and improves glucose homeostasis. AD-9308 can be used in studies related to acrolein-induced kidney injury, diabetes, cardiomyopathy, heart failure, diet-induced obesity, fatty liver, insulin resistance and glucose intolerance.
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- No. CAS: 1804942-56-0
- Fòrmula: C30H36FN3O5
- Peso molecular:537.62
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Actividad biológica
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Chemical Information
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Actividad biológica
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ALDH2 |
IL-6 |
AD-9308 activates both wild-type and ALDH2E487K mutant ALDH2 proteins[1].
AD-9308 (100 μM) activates recombinant wild-type human ALDH2 protein via its active metabolite AD-5591, increasing the enzyme activity to approximately 1600 μmol NADH/min/mg protein[5].
AD-9308 alleviates acrolein-induced ferroptosis and mitochondrial dysfunction, and enhances the cell viability of primary mouse proximal tubular epithelial cells with Aldh2-WT and Aldh22/2, via its active metabolite AD-5591 (10 μM; 1 h pre-incubation)[1].
AD-9308 (preincubated for 1 h; incubated for 72 h under high glucose/high palmitic acid conditions) maintains the viability and ATP production of H9c2 cardiomyocytes and inhibits cell apoptosis under high glucose and high palmitic acid conditions[2].
AD-9308 (5-10 μM; 1 h pre-incubation; 72 h incubation under high-glucose/high-palmitate conditions) inhibits NF-κB activation in H9c2 cardiac fibroblasts under high-glucose and high-palmitate conditions by stabilizing IκBα and reducing p65 nuclear translocation[2].
AD-9308 (incubated under high glucose/high palmitate conditions) improves mitochondrial respiratory function of H9c2 cardiomyocytes under high glucose and high palmitate conditions[2].
AD-9308 (5-10 μM; incubation under high-glucose/high-palmitate conditions; 30 min Fura-2-AM loading) restores SR/ER Ca2+ levels in H9c2 cardiomyoblasts exposed to a high-glucose and high-fat environment[2].
AD-9308 (the active form of AD-5591) (20 μM; 16 h) restores ALDH2 activity, alleviates oxidative stress, rescues angiogenic function, restores eNOS activity, and reduces the secretion of pro-inflammatory/pro-proliferative cytokines in human pulmonary artery endothelial cells treated with the ALDH2 inhibitors daidzein and 4-hydroxynonenal[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
AD-9308 (60-180 mg/kg/day; p.o.; daily; ~4 months) dose-dependently improves left ventricular diastolic and systolic function, mitigates cardiac structural remodeling, reduces oxidative stress, fibrosis, inflammation, and apoptosis, and restores mitochondrial function in Streptozotocin (HY-13753)-induced diabetic Mus musculus, with significant linear trends observed across multiple efficacy endpoints[2].
AD-9308 (40 mg/kg/day; oral gavage; twice daily; six weeks) restores Dicer activity, reduces cardiac remodelling, and improves left ventricular ejection fraction in myocardial infarction-induced heart failure in Rattus norvegicus via enhanced ALDH2-mediated 4-HNE clearance[3].
AD-9308 (60 mg/kg; p.o.; daily; 4 weeks) mitigates hypoxia-induced pulmonary hypertension in heterozygous ALDH21/2 knock-in mice by reducing right ventricular systolic pressure, right ventricular hypertrophy, pulmonary arterial remodeling, oxidative stress, 4-HNE-protein adduct accumulation, and endothelial IL-6 association[4].
AD-9308 (20-60 mg/kg/day; p.o.; daily; 20 weeks) dose-dependently attenuates diet-induced obesity, fatty liver, insulin resistance, and glucose intolerance in male C57BL/6J Aldh2 wild-type mice by reducing serum 4-HNE levels[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6J Aldh22/2 (Glu504Lys knock-in) (male, 6 weeks old, chronic oral acrolein-induced renal injury)[1]
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Dosage:20 mg/kg
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Administration:p.o.; daily; 12 consecutive weeks
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Result:Markedly reduced acrolein-induced increases in urine albumin-to-creatinine ratio (UACR) and blood urea nitrogen (BUN) levels.
Ameliorated acrolein-induced tubular damage including vacuolar degeneration, epithelial swelling, tubular dilation, and interstitial fibrosis.
Reversed acrolein-induced kidney GSH depletion, reduced acrolein-increased renal ferrous iron (Fe2+) accumulation, and lowered elevated renal malondialdehyde (MDA) levels.
Substantially attenuated acrolein-induced increases in renal acrolein-protein conjugates (Acr-PC), neutrophil gelatinase-associated lipocalin (NGAL), fibronectin, and alpha-smooth muscle actin (α-SMA) protein expression.
Reduced acrolein-induced upregulation of mRNA expression for tubular injury markers (NGAL, KIM-1) and pro-inflammatory cytokines (IL-6, TGF-β).
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Animal Model:C57BL6/J mice (8-week-old at study initiation; streptozotocin-induced hyperglycemia)[2]
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Dosage:60 mg/kg/day; 180 mg/kg/day
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Administration:p.o.; daily; ~4 months
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Result:Improved left ventricular diastolic function with significant linear trends for E/A ratio (p-for-trend = 0.0180), e’ wave velocity (p-for-trend = 0.0002), E/e’ ratio (p-for-trend = 0.0202), e’/a’ ratio (p-for-trend = 0.0019), and isovolumic relaxation time (p-for-trend = 0.0107).
Improved systolic function with significant linear trends for fractional shortening (p-for-trend = 0.0055), ejection fraction (p-for-trend = 0.0042), stroke volume (p-for-trend = 0.0006), cardiac output (p-for-trend = 0.0004), and s wave velocity (p-for-trend = 0.0167).
Mitigated reductions in interventricular septum thickness at end diastole (p-for-trend = 0.0022) and left ventricular mass (p-for-trend = 0.0015).
Reduced serum 4-hydroxy-2-nonenal (4-HNE) levels, cardiac tissue 4-HNE protein adducts, and cardiac heme oxygenase 1 (Ho-1) expression.
Enhanced cardiac ALDH2 enzymatic activity.
Reduced cardiac mRNA expression of fibrosis markers Tgf-β1 (p-for-trend < 0.0001), Ctgf (p-for-trend < 0.0001), Fsp1 (p-for-trend = 0.0026), Postn (p-for-trend = 0.0046), Fn-1 (p-for-trend = 0.0001), and Tgf-β2 (p-for-trend = 0.0004), as well as α-Sma (p-for-trend = 0.0367) and Col IV (p-for-trend = 0.0113) mRNA and protein deposition.
Reduced cardiac mRNA expression of inflammatory markers Il-1β (p-for-trend = 0.0010), Il-6 (p-for-trend = 0.0002), Infγ (p-for-trend = 0.0054), Mcp-1 (p-for-trend = 0.0047), Sap (p-for-trend = 0.0005), and Tnf-α (p-for-trend < 0.0001).
Increased cardiac Bcl-2 expression, reduced iNOS, Bax, and cleaved caspase 3 expression, stabilized IκBα protein, and reduced NF-κB p65 nuclear translocation and activity.
Improved cardiac mitochondrial electron transfer chain complex II and III activities, reversed diabetic shifts in mitochondrial dynamic regulators (reduced Drp1, normalized Opa1 processing), and lowered cardiac autophagy markers Beclin 1 and LC3A/B II expression.
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Animal Model:Wistar normotensive male rats (12 weeks of age at study initiation; myocardial infarction-induced heart failure model)[3]
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Dosage:40 mg/kg/day
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Administration:oral gavage; twice daily; six weeks
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Result:Restored cardiac Dicer activity to levels comparable to vehicle-treated sham rats.
Reduced left ventricular end-diastolic diameter, cardiomyocyte cross-sectional area, left ventricular fibrosis, and inflammatory cell infiltration compared to vehicle-treated heart failure controls.
Improved left ventricular ejection fraction, re-established cardiac ALDH2 catalytic activity, and reduced cardiac 4-HNE protein adduct levels in heart failure rats.
Showed no significant effects on cardiac morphology, function, aldehyde clearance, or Dicer function in sham-treated rats.
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Animal Model:heterozygous ALDH2*1/*2 knock-in (male, 10-week-old, chronic 10% O2 hypoxia for 4 weeks induced pulmonary hypertension)[4]
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Dosage:60 mg/kg
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Administration:p.o.; daily; 4 weeks
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Result:Significantly reduced hypoxia-induced increases in right ventricular systolic pressure.
Reduced the Fulton index (right ventricular hypertrophy marker).
Restored lung superoxide dismutase activity.
Decreased the percentage of pulmonary arterial wall thickness.
Lowered the signal intensity of 4-HNE-protein adducts in pulmonary arteries.
Attenuated hypoxia-induced increases in proximity ligation assay signal (indicating reduced interleukin-6 association with pulmonary arterial endothelial cells).
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Animal Model:C57BL/6J Aldh2 wild-type (male; fed high-fat high-sucrose diet from 10 weeks of age)[5]
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Dosage:20 mg/kg/day; 60 mg/kg/day
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Administration:p.o.; daily; 20 weeks
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Result:Reduced diet-induced weight gain dose-dependently.
Decreased weights of perigonadal fat, inguinal fat, and omental fat.
Reduced adipocyte hypertrophy.
Decreased hepatic steatosis severity and hepatic triglyceride levels.
Lowered fasting glucose levels.
Improved insulin sensitivity and glucose tolerance.
Reduced serum 4-hydroxynonenal (4-HNE) levels.
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Animal Model:C57BL/6J Aldh2 homozygous knock-in (male; mimicking human Glu504Lys mutation; fed high-fat high-sucrose diet from 10 weeks of age)[5]
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Dosage:20 mg/kg/day; 60 mg/kg/day
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Administration:p.o.; daily; 20 weeks
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Result:Reduced diet-induced weight gain dose-dependently.
Decreased weights of perigonadal fat, inguinal fat, and omental fat.
Reduced adipocyte hypertrophy.
Decreased hepatic steatosis severity and hepatic triglyceride levels.
Lowered fasting glucose levels.
Improved insulin sensitivity and glucose tolerance.
Reduced serum 4-hydroxynonenal (4-HNE) levels.
Reduced the number of 4-HNE-adducted mitochondrial proteins involved in fatty acid oxidation and electron transport chain in brown adipose tissue.
Chemical Information
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No. CAS 1804942-56-0
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Peso molecular 537.62
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Fòrmula C30H36FN3O5
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SMILES
CC(C)[C@H](N)C(OCC1=C(C2=CC(C(NCC3=CC(F)=C(C=C3)OC)=O)=C(C=C2)OCC(C)C)N=CC=C1)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[1]. Kuo YM, et al. Aldehyde dehydrogenase 2 mitigates acrolein-driven ferroptosis to preserve kidney function. Environmental pollution (Barking, Essex : 1987). 2026 Feb 01;390:127555. [Content Brief]
[2]. Lee HL, et al. A Novel ALDH2 Activator AD-9308 Improves Diastolic and Systolic Myocardial Functions in Streptozotocin-Induced Diabetic Mice. Antioxidants (Basel, Switzerland). 2021 Mar 13;10(3):450. [Content Brief]
[3]. Kiyuna LA, et al. 4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification. European heart journal. 2023 Nov 21;44(44):4696-4712. [Content Brief]
[4]. Chou YH, et al. Deciphering endothelial aldehyde dehydrogenase 2, oxidative stress, and interleukin-6 interactions in pulmonary hypertension: Implications for precision medicine. Biochemical pharmacology. 2026 Jan;243(Pt 1):117510. [Content Brief]
[5]. Chang YC, et al. A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators. Nature communications. 2023 Sep 25;14(1):5971. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
AD-9308 Related Classifications
HY-160475 Related Classifications
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- AD-9308
- 1804942-56-0
- AD9308
- AD 9308
- Aldehyde Dehydrogenase (ALDH)
- Interleukin Related
- acrolein
- C57BL/6J Aldh2 wild-type mice
- aldehyde dehydrogenase 2
- myocardial infarction-induced heart failure
- H9c2 cardiomyoblasts
- 4-hydroxy-2-nonenal
- human pulmonary arterial endothelial cells
- streptozotocin-induced diabetic mice
- Inhibitor
- inhibitor
- inhibit