Emixustat (ACU-4429)
(Synonyms: ACU-4429) 目录号 : GC31373
Emixustat(ACU-4429) is a first in class small-molecule visual cycle modulator that inhibits the isomerase complex.
Cas No.:1141777-14-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Animal experiment [1]: |
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Animal models |
BALB/c mice (8 weeks) |
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Preparation method |
Dark-adapted (12 hours) BALB/c mice (8 weeks, n = 4/group) were orally dosed with emixustat (0.01-3.0 mg/kg) or vehicle (water). At 4 hours post-dose, animals were photobleached (5000 lux white light, 10 min) without anesthesia or mydriatics, returned to the dark for 2 hours, and then euthanized under red light. |
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Dosage form |
0.01-3.0 mg/kg; p.o |
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Applications |
Emixustat was found to reduce the production of visual chromophore (11-cis retinal) in wild-type mice following a single oral dose (ED50 = 0.18 mg/kg). |
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References: [1]. Bavik C, Henry SH,et,al. Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity. PLoS One. 2015 May 13;10(5):e0124940. doi: 10.1371/journal.pone.0124940. PMID: 25970164; PMCID: PMC4430241. |
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Emixustat(ACU-4429) is a first in class small-molecule visual cycle modulator that inhibits the isomerase complex. As an inhibitor of visual cycle isomerase, the IC50 value is 4.4 nM[1].
Emixustat strongly inhibits 11-cis-retinol production with an IC50 value of 232±3 nM[2]. A concentration-dependent reduction of 11-cis-ROL production (i.e., inhibition of RPE65 isomerase activity) by emixustat(10-5 to 10-10 M)[1].
Emixustat(0.01-3.0 mg/kg; p.o) was found to reduce the production of visual chromophore (11-cis retinal) in wild-type mice following a single oral dose (ED50 = 0.18 mg/kg) [1]. In 40 subjects (mean age, 38 years) Emixustat (n = 30) (5, 10, 20, 30, or 40 mg; 14-day) was rapidly absorbed (median T(max), 3.0-5 hours) and readily eliminated (mean t(1/2), 4.6-7.9 hours), and mean C(max) generally increased in proportion to dose. Systemic adverse events were minimal[3]. Emixustat significantly abates permeability after Ischemia Reperfusion(IR) on vascular permeability in mice[4].
Emixustat(ACU-4429)是一种抑制异构酶复合物的小分子视觉周期调节剂。作为视循环异构酶抑制剂,IC50值为4.4 nM[1]。
Emixustat抑制11-顺式视黄醇的产生,IC50值为232±3 nM[2]。Emixustat (10-5 ~ 10-10 M) 以浓度依赖性降低11-cis-ROL的产量 (即抑制RPE65异构酶活性) [1]。
研究发现,单次口服Emixustat (0.01-3.0 mg/kg; p.o)可减少野生型小鼠视觉发色团(11-cis retinal)的产生(ED50 = 0.18 mg/kg)[1]。40名受试者(平均年龄38岁)。Emixustat (n = 30)(5-40 mg;14days)吸收迅速(中位值3.0-5小时),容易消除(平均时间4.6-7.9小时),平均峰浓度随剂量成比例增加。不良事件极少[3]。Emixustat显著降低小鼠缺血再灌注后血管通透性[4]。
References:
[1]. Bavik C, Henry SH, et,al.Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity. PLoS One. 2015 May 13;10(5):e0124940. doi: 10.1371/journal.pone.0124940. PMID: 25970164; PMCID: PMC4430241.
[2]. Kiser PD, Zhang J, et,al.Catalytic mechanism of a retinoid isomerase essential for vertebrate vision. Nat Chem Biol. 2015 Jun;11(6):409-15. doi: 10.1038/nchembio.1799. Epub 2015 Apr 20. PMID: 25894083; PMCID: PMC4433804.
[3].Kubota R, Al-Fayoumi S, et,al. Phase 1, dose-ranging study of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in healthy volunteers. Retina. 2014 Mar;34(3):603-9. doi: 10.1097/01.iae.0000434565.80060.f8. PMID: 24056528.
[4].Dreffs A, Lin CM, et,al. All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion. Invest Ophthalmol Vis Sci. 2020 Jun 3;61(6):8. doi: 10.1167/iovs.61.6.8. PMID: 32492112; PMCID: PMC7415894.
| Cas No. | 1141777-14-1 | SDF | |
| 别名 | ACU-4429 | ||
| Canonical SMILES | O[C@H](CCN)C1=CC(OCC2CCCCC2)=CC=C1 | ||
| 分子式 | C16H25NO2 | 分子量 | 263.38 |
| 溶解度 | DMSO : ≥ 43 mg/mL (163.26 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.7968 mL | 18.984 mL | 37.968 mL |
| 5 mM | 0.7594 mL | 3.7968 mL | 7.5936 mL |
| 10 mM | 0.3797 mL | 1.8984 mL | 3.7968 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
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一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Bioanalysis of emixustat (ACU-4429) in whole blood collected with volumetric absorptive microsampling by LC-MS/MS
Background: A method to quantify emixustat (an investigational drug agent) in human blood collected using volumetric absorptive microsampling (VAMS) could be more practical for sample collection at sites with limited facilities for processing and storage of plasma. Methods: A LC-MS/MS method was developed and evaluated for accuracy and precision, linearity, carryover, selectivity, recovery, matrix effects, hematocrit effects and stability. Results: Core validation parameters met acceptance criteria within the normal ranges of hematocrit levels for adults (30-55%). Stability of emixustat in blood collected with and without anticoagulant (NaF/KOx) on the VAMS device at ambient, refrigerated and frozen conditions was established. Conclusion: The method has been validated and is suitable for the bioanalysis of emixustat in human blood collected by VAMS.
Phase 1, dose-ranging study of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in healthy volunteers
Background: Emixustat hydrochloride (formerly ACU-4429) is a nonretinoid compound with a unique mode of action in the retinal pigment epithelium, where it modulates the biosynthesis of visual chromophore through its effect on retinal pigment epithelium-specific 65 kDa protein isomerase. This study provides clinicians with a background for understanding the pharmacokinetics and safety profile of orally administered emixustat.
Methods: This randomized, double-masked, placebo-controlled Phase 1b study evaluated the pharmacokinetics, tolerability, and safety of a 14-day course of oral emixustat (5, 10, 20, 30, or 40 mg) or placebo (3:1 ratio) once daily in healthy volunteers.
Results: A total of 40 subjects were enrolled (mean age, 38 years; 75% male). Emixustat (n = 30) was rapidly absorbed (median T(max), 3.0-5 hours) and readily eliminated (mean t(1/2), 4.6-7.9 hours), and mean C(max) and AUC(0-24) generally increased in proportion to dose. No significant accumulation of emixustat was observed with multiple-dose administration. Ocular adverse events occurred in 67% of the subjects who received emixustat; all were considered mild and resolved after study completion. Systemic adverse events were minimal.
Conclusion: Oral emixustat was safe and well tolerated when administered once daily for 14 days with minimal systemic adverse events reported. These data support evaluation of emixustat in subjects with geographic atrophy associated with dry age-related macular degeneration.
Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity
Increased exposure to blue or visible light, fluctuations in oxygen tension, and the excessive accumulation of toxic retinoid byproducts places a tremendous amount of stress on the retina. Reduction of visual chromophore biosynthesis may be an effective method to reduce the impact of these stressors and preserve retinal integrity. A class of non-retinoid, small molecule compounds that target key proteins of the visual cycle have been developed. The first candidate in this class of compounds, referred to as visual cycle modulators, is emixustat hydrochloride (emixustat). Here, we describe the effects of emixustat, an inhibitor of the visual cycle isomerase (RPE65), on visual cycle function and preservation of retinal integrity in animal models. Emixustat potently inhibited isomerase activity in vitro (IC50 = 4.4 nM) and was found to reduce the production of visual chromophore (11-cis retinal) in wild-type mice following a single oral dose (ED50 = 0.18 mg/kg). Measure of drug effect on the retina by electroretinography revealed a dose-dependent slowing of rod photoreceptor recovery (ED50 = 0.21 mg/kg) that was consistent with the pattern of visual chromophore reduction. In albino mice, emixustat was shown to be effective in preventing photoreceptor cell death caused by intense light exposure. Pre-treatment with a single dose of emixustat (0.3 mg/kg) provided a ~50% protective effect against light-induced photoreceptor cell loss, while higher doses (1-3 mg/kg) were nearly 100% effective. In Abca4-/- mice, an animal model of excessive lipofuscin and retinoid toxin (A2E) accumulation, chronic (3 month) emixustat treatment markedly reduced lipofuscin autofluorescence and reduced A2E levels by ~60% (ED50 = 0.47 mg/kg). Finally, in the retinopathy of prematurity rodent model, treatment with emixustat during the period of ischemia and reperfusion injury produced a ~30% reduction in retinal neovascularization (ED50 = 0.46mg/kg). These data demonstrate the ability of emixustat to modulate visual cycle activity and reduce pathology associated with various biochemical and environmental stressors in animal models. Other attributes of emixustat, such as oral bioavailability and target specificity make it an attractive candidate for clinical development in the treatment of retinal disease.
Stargardt macular dystrophy and evolving therapies
Introduction: Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that lacks effective treatment options. Gene therapy, stem cell therapy, and pharmacotherapy with visual cycle modulators (VCMs) and complement inhibitors are discussed as potential treatments.
Areas covered: Investigational therapies for STGD1 aim to reduce toxic bisretinoids and lipofuscin in the retina and retinal pigment epithelium (RPE). These agents include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Avacincaptad pegol is a C5 complement inhibitor that may reduce inflammation-related RPE damage. Animal models of STGD1 show promising data for these treatments, though proof of efficacy in humans is lacking. Fenretinide and emixustat are VCMs for dry AMD and STGD1 that failed to halt geographic atrophy progression or improve vision in trials for AMD. A1120 prevents retinol transport into RPE and may spare side effects typically seen with VCMs (nyctalopia and chromatopsia). Stem cell transplantation suggests potential biologic plausibility in a phase I/II trial. Gene therapy aims to augment the mutated ABCA4 gene, though results of a phase I/II trial are pending.
Expert opinion: Stem cell transplantation, ABCA4 gene therapy, VCMs, and complement inhibitors offer biologically plausible treatment mechanisms for treatment of STGD1. Further trials are warranted to assess efficacy and safety in humans.
Pharmacotherapy for metabolic and cellular stress in degenerative retinal diseases
Retinal photoreceptors continually endure stresses associated with prolonged light exposure and the metabolic demands of dark adaptation. Although healthy photoreceptors are able to withstand these stresses for several decades, the disease-affected retina functions at a reduced capacity and is at an increased risk for dysfunction. To alleviate cellular and metabolic stressors in degenerative retinal diseases, a new class of drugs that modulate the metabolic activity of the retina have been developed. A clinical candidate in this class (emixustat) has been shown to reduce retinal pathology in various animal models of human retinal disease and is currently under clinical study. Here, we describe the pharmacological properties of emixustat, its mechanisms of action, and potential for use in the treatment of specific retinal diseases.