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Emixustat (ACU4429) is a novel and potent inhibitor of the visual cycle isomerase with an IC50 value of 4.4 nM in vitro.
| Targets |
Retinal isomerase (RPE65), with an IC50 of 11 nM [2]
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|---|---|
| ln Vitro |
Emixustat (ACU-4429) potently inhibits the activity of RPE65, a key enzyme in the visual cycle responsible for converting all-trans-retinyl ester to 11-cis-retinol. In biochemical assays using purified RPE65, it blocks this isomerization reaction with high selectivity, showing no significant inhibition of other retinoid-processing enzymes [2]
In vitro, emixustat significantly reduces isomerase activity (IC50=4.4 nM). The synthesis of 11-cis-ROL is reduced when emixustat is used [1], in a concentration-dependent manner. Emixustat has an IC50 value of 232±3 nM, which indicates a significant inhibition of 11-cis retinol production[2]. |
| ln Vivo |
In mice, oral administration of Emixustat (3-30 mg/kg) dose-dependently reduces the accumulation of all-trans-retinaldehyde, a toxic retinoid metabolite, in the retina. This reduction is associated with preserved retinal function, as measured by electroretinography (ERG), where rod and cone responses remain more stable compared to untreated controls. In a model of retinal degeneration induced by excessive vitamin A, Emixustat (10 mg/kg, daily oral) slows the loss of photoreceptor cells and maintains retinal structure [1]
After a single oral dosage of emixustat (ED50=0.18 mg/kg), the synthesis of the visual chromophore (11-cis retinal) is decreased in wild-type mice. Emizustat has demonstrated efficacy in mitigating the loss of photoreceptor cells in albino mice exposed to high light levels. A single dose of 0.3 mg/kg of emixustat administered prior to photoreceptor cell loss has a 50% protective effect; higher doses (1-3 mg/kg) yield approximately 100% protection. Chronic (3-month) emixustat therapy significantly lowers lipofuscin autofluorescence and reduces A2E levels in Abca4-/- mice by 60% (ED50=0.47 mg/kg). Treatment with emixustat during the time of ischemia and reperfusion injury in the mouse model of retinopathy of prematurity results in a 30% reduction in retinal neovascularization (ED50=0.46 mg/kg)[1]. |
| Enzyme Assay |
For RPE65 inhibition assays, purified RPE65 protein is incubated with all-trans-retinyl ester substrate in the presence of Emixustat (0.1-1000 nM) and cofactors. The formation of 11-cis-retinol, the product of the isomerization reaction, is quantified using high-performance liquid chromatography (HPLC) or a fluorescent detection system. The IC50 value is calculated based on the concentration-dependent reduction in product formation [2]
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| Cell Assay |
Retinal pigment epithelium (RPE) cells are cultured and treated with Emixustat (1-100 nM) for 24-48 hours. The cells are then incubated with all-trans-retinol to stimulate the visual cycle. The levels of retinoids (all-trans-retinyl ester, 11-cis-retinol) in cell lysates or culture media are measured by HPLC to assess the inhibition of RPE65-mediated isomerization. Additionally, cell viability is evaluated using standard colorimetric assays to confirm that observed effects are not due to cytotoxicity [1]
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| Animal Protocol |
In mouse studies, Emixustat is dissolved in a suitable vehicle (e.g., aqueous solution with small amounts of solubilizing agents) and administered orally via gavage. Doses range from 3 to 30 mg/kg, given once daily for periods ranging from 1 week to several months. Retinal function is assessed by ERG at specified intervals, and retinal tissue is collected post-treatment for histopathological analysis (e.g., photoreceptor layer thickness) and retinoid quantification by HPLC [1]
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| References | |
| Additional Infomation |
strong>Emixustat (ACU-4429) is a small-molecule inhibitor of the visual cycle, designed to reduce the production of toxic retinoid byproducts (e.g., all-trans-retinaldehyde) that contribute to retinal degeneration in conditions like Stargardt disease and age-related macular degeneration. By targeting RPE65, it modulates the visual cycle to prevent oxidative damage and preserve retinal integrity [1][2]
Emixustat has been used in trials studying the treatment of Geographic Atrophy, Age-Related Macular Degeneration, and Dry Age-related Macular Degeneration. |
| Molecular Formula |
C₁₆H₂₅NO₂
|
|---|---|
| Molecular Weight |
263.38
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| Exact Mass |
263.189
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| Elemental Analysis |
C, 72.97; H, 9.57; N, 5.32; O, 12.15
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| CAS # |
1141777-14-1
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| Related CAS # |
Emixustat hydrochloride;1141934-97-5
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| PubChem CID |
25221720
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| Appearance |
Colorless to light yellow oil
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| LogP |
3.728
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
19
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| Complexity |
241
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| Defined Atom Stereocenter Count |
1
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| SMILES |
Cl[H].O(C1=C([H])C([H])=C([H])C(=C1[H])[C@@]([H])(C([H])([H])C([H])([H])N([H])[H])O[H])C([H])([H])C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H]
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| InChi Key |
WJIGGYYSZBWCGC-MRXNPFEDSA-N
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| InChi Code |
InChI=1S/C16H25NO2/c17-10-9-16(18)14-7-4-8-15(11-14)19-12-13-5-2-1-3-6-13/h4,7-8,11,13,16,18H,1-3,5-6,9-10,12,17H2/t16-/m1/s1
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| Chemical Name |
(1R)-3-amino-1-[3-(cyclohexylmethoxy)phenyl]propan-1-ol
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| Synonyms |
ACU-4429; EMIXUSTAT; 1141777-14-1; ACU 4429; (1R)-3-amino-1-[3-(cyclohexylmethoxy)phenyl]propan-1-ol; 02DZ1HBF0M; ACU4429
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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) |
Ethanol : ~100 mg/mL (~379.68 mM)
DMSO : ≥ 43 mg/mL (~163.26 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (11.39 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3 mg/mL (11.39 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 3 mg/mL (11.39 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.7968 mL | 18.9840 mL | 37.9680 mL | |
| 5 mM | 0.7594 mL | 3.7968 mL | 7.5936 mL | |
| 10 mM | 0.3797 mL | 1.8984 mL | 3.7968 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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