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| Targets |
The primary target of OAB-14 is the retinoid X receptor (RXR). Upon RXR activation, OAB-14 modulates the expression of genes involved in Abeta clearance pathways, including endosomal-autophagic-lysosomal (EAL) system components. Unlike the RXR agonist bexarotene, which showed no effect on neprilysin (NEP) or insulin-degrading enzyme (IDE) levels, OAB-14 enhances autophagic clearance of Abeta through the AMPK/mTOR pathway, thereby reducing neuroinflammation and amyloid deposition.
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| ln Vitro |
In vitro, OAB-14 is a bexarotene derivative that reduces neuroinflammation and modulates Abeta metabolism. It enhances endosomal-autophagic-lysosomal function and restores autophagy flux through modulation of the AMPK/mTOR signaling pathway. This mechanism promotes the clearance of intracellular and extracellular Abeta aggregates, reducing the accumulation of neurotoxic Abeta species. OAB-14 also reduces the levels of hyperphosphorylated tau (p-tau), another key pathological feature of Alzheimer‘s disease.
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| ln Vivo |
After being administered for 15 days or 3 months, OAB-14 dramatically reduced the cognitive deficits in transgenic mice that were APP/PS1 positive. By encouraging microglia phagocytosis and elevating the expression of IDE and NEP, OAB-14 quickly removed 71% of Aβ. In APP/PS1 mice, OAB-14 also reduces the negative consequences of Aβ buildup, including neuroinflammation, neuronal loss, and synaptic degeneration. Both acute and long-term treatment of OAB-14 does not significantly affect body weight or liver damage [1]. Through the AMPK/mTOR pathway, OAB-14 promotes receptor-mediated endocytosis and reestablishes autophagy flux. OAB-14 increases lysosomal activity, and AD animals treated with OAB-14 show decreased Aβ buildup in lysosomes[2].
In vivo, OAB-14 (oral administration) improves Alzheimer's disease-related pathologies and cognitive impairments by increasing beta-amyloid clearance in APP/PS1 transgenic mice. OAB-14 treatment reduces brain amyloid plaque burden and lowers levels of soluble Abeta40 and Abeta42. The compound also reduces neuroinflammation as evidenced by decreased glial activation and pro-inflammatory cytokine levels. OAB-14 demonstrates high safety in animal models, and the structurally related RXR agonist bexarotene has been shown to enhance clearance of soluble Abeta within hours in an apoE-dependent manner. |
| Enzyme Assay |
The binding affinity of OAB-14 for RXR can be determined using a radioligand binding assay. Nuclear extracts from cells expressing human RXRalpha are incubated with [3H]9-cis-retinoic acid (a RXR agonist) and varying concentrations of OAB-14 in binding buffer for 2-4 hours at 4degC. Bound and free radioligand are separated using a charcoal-dextran method or by filtration, and radioactivity is counted. Non-specific binding is determined with a 200-fold excess of unlabeled bexarotene.
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| Cell Assay |
For cellular assays, primary microglial cells or neuronal cell lines (e.g., BV-2, N2a) are treated with OAB-14 (e.g., 0.1-10 uM) for 24-48 hours. The expression of autophagy markers (LC3-II, p62) is assessed by Western blot to evaluate autophagic flux. Alternatively, cells are treated with Abeta oligomers (5 uM) in the presence of OAB-14, and intracellular Abeta levels are quantified by ELISA to assess clearance. For AMPK/mTOR pathway analysis, phospho-AMPK and phospho-mTOR levels are measured by Western blot.
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| Animal Protocol |
In an in vivo protocol, male or female APP/PS1 transgenic mice (5-8 months old) are administered OAB-14 orally (e.g., 10-50 mg/kg/day) or via intraperitoneal injection for 4-8 weeks. After treatment, behavioral tests are performed: Morris water maze for learning and memory, open field for locomotor activity, and novel object recognition for short-term memory. Following behavioral testing, mice are euthanized, and brain tissue is collected for analysis of Abeta levels (by ELISA), amyloid plaque burden (by Thioflavin S staining), and glial activation (by Iba1 and GFAP immunohistochemistry).
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| ADME/Pharmacokinetics |
Specific pharmacokinetic data for OAB-14 is not provided, but it is described as an orally active compound that reaches the brain. The structurally related RXR agonist bexarotene is well-absorbed orally, has a half-life of approximately 7 hours in humans, and crosses the blood-brain barrier. OAB-14 is a small molecule (molecular weight approximately 518.7 g/mol) with moderate lipophilicity, which should facilitate brain penetration. OAB-14 demonstrated high safety in preclinical studies and was well-tolerated at effective doses in animal models.
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| Toxicity/Toxicokinetics |
OAB-14 has shown promising efficacy and high safety in preclinical studies, with no significant adverse effects reported at pharmacologically active doses in mouse models. The compound was developed as a bexarotene derivative with an improved safety and efficacy profile for the treatment of Alzheimer's disease. Unlike bexarotene, which is approved for the treatment of cutaneous T-cell lymphoma but has shown mixed results in AD models, OAB-14 was specifically designed to enhance amyloid clearance while avoiding the metabolic and thyroid-related side effects associated with the parent compound. It improves Alzheimer‘s disease-related pathologies and cognitive impairments by increasing beta-amyloid clearance, reducing neuroinflammation, and restoring endosomal-autophagic-lysosomal function in APP/PS1 mice. OAB-14 is a valuable research tool for studying the role of RXR signaling and autophagic clearance mechanisms in the pathogenesis and treatment of Alzheimer's disease.
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| References |
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| Molecular Formula |
C32H46N4O2
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| Molecular Weight |
518.733248233795
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| Exact Mass |
518.362
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| CAS # |
2140911-49-3
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| PubChem CID |
132051020
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| Appearance |
White to off-white solid powder
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| LogP |
7.1
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
38
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| Complexity |
829
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C=CC(=CC=1)NC(NCCN)=O)NC1=C2C(=CC3=C1C(C)(C)CCC3(C)C)C(C)(C)CCC2(C)C
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| InChi Key |
LWZSVUPSOLLTIN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H46N4O2/c1-29(2)13-15-31(5,6)24-22(29)19-23-25(32(7,8)16-14-30(23,3)4)26(24)36-27(37)20-9-11-21(12-10-20)35-28(38)34-18-17-33/h9-12,19H,13-18,33H2,1-8H3,(H,36,37)(H2,34,35,38)
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| Chemical Name |
4-(2-aminoethylcarbamoylamino)-N-(1,1,4,4,5,5,8,8-octamethyl-2,3,6,7-tetrahydroanthracen-9-yl)benzamide
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: 20 mg/mL (38.56 mM)
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| 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 | 1.9278 mL | 9.6389 mL | 19.2779 mL | |
| 5 mM | 0.3856 mL | 1.9278 mL | 3.8556 mL | |
| 10 mM | 0.1928 mL | 0.9639 mL | 1.9278 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.
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