Emixustat hydrochloride (ACU-4429 hydrochloride)
(Synonyms: ACU-4429 hydrochloride) 目录号 : GC33763
An RPE65 inhibitor
Cas No.:1141934-97-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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ACU 4429 is an inhibitor of retinal pigment epithelium 65 (RPE65; IC50 = 4.4 nM), an enzyme that catalyzes the isomerization of 11-trans retinol to 11-cis retinol in the visual cycle.1 It reduces rod photoreceptor recovery in dark-adapted mice after photobleaching (ED50 = 0.21mg/kg) and reversibly decreases the regeneration of 11-cis retinal oxime in the same model (ED50 = 0.18 mg/kg). ACU 4429 also prevents light-induced photoreceptor cell loss in dark-adapted albino mice. It reduces lipofuscin autofluorescence and decreases the level of retinoid toxin (A2E) in the RPE in an Abca4-/- mouse model of Stargardt disease (ED50 = 0.47 mg/kg).
1.Bavik, C., Henry, S.H., Zhang, Y., et al.Visual cycle modulation as an approach toward preservation of retinal integrityPLoS One10(5)e0124940(2015)
| Cas No. | 1141934-97-5 | SDF | |
| 别名 | ACU-4429 hydrochloride | ||
| Canonical SMILES | O[C@H](CCN)C1=CC(OCC2CCCCC2)=CC=C1.[H]Cl | ||
| 分子式 | C16H26ClNO2 | 分子量 | 299.84 |
| 溶解度 | DMSO : ≥ 44 mg/mL (146.74 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 | 3.3351 mL | 16.6756 mL | 33.3511 mL |
| 5 mM | 0.667 mL | 3.3351 mL | 6.6702 mL |
| 10 mM | 0.3335 mL | 1.6676 mL | 3.3351 mL |
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| 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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；
2.
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。
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.PMID:24056528DOI:10.1097/01.iae.0000434565.80060.f8.
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.
Emixustat hydrochloride for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Clinical Trial
Ophthalmology 2018 Oct;125(10):1556-1567.PMID:29716784DOI:10.1016/j.ophtha.2018.03.059.
Purpose: To determine whether Emixustat hydrochloride (emixustat) reduces the rate of enlargement of geographic atrophy (GA) compared with placebo in subjects with age-related macular degeneration (AMD) and to evaluate the safety and tolerability of emixustat over 24 months of treatment. Design: Multicenter, randomized, double-masked, placebo-controlled, phase 2b/3 clinical trial. Participants: Patients with GA secondary to AMD, a visual acuity score of at least 35 letters, and GA with a total area of 1.25 to 18 mm2 were enrolled. Methods: Subjects were randomized (1:1:1:1) to emixustat 2.5 mg, 5 mg, 10 mg, or placebo, administered orally once daily for 24 months. Visits included screening, baseline, and months 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, and 25. Main outcome measures: The primary efficacy end point was the mean annual growth rate of total GA area in the study eye, as measured by a central reading center using fundus autofluorescence (FAF) images. The change from baseline in normal luminance best-corrected visual acuity (NL-BCVA) was a secondary efficacy end point. Results: Of 508 randomized subjects, 320 completed the study. Demographics and baseline characteristics were comparable between treatment groups. On average, GA lesions in the study eye grew at a similar rate in each group (emixustat: 1.69 to 1.84 mm2/year; placebo: 1.69 mm2/year; P ≥ 0.81). Changes in NL-BCVA were also comparable between groups. Subjects with a larger low luminance deficit (LLD) at baseline (≥20 letters) demonstrated a more rapid growth of GA over 24 months. No relationship was observed between the risk-allele status of the AMD-associated single-nucleotide polymorphisms tested and the growth rate of GA. The most common adverse events in emixustat-treated subjects were delayed dark adaptation (55%), chromatopsia (18%), visual impairment (15%), and erythropsia (15%). Conclusions: Emixustat did not reduce the growth rate of GA in AMD. The most common adverse events were ocular in nature and likely related to the drug's mechanism of action. Data gained from this study over a 2-year period add to the understanding of the natural history of GA and the baseline characteristics affecting the growth rate of GA.
Effects of Emixustat hydrochloride in patients with proliferative diabetic retinopathy: a randomized, placebo-controlled phase 2 study
Graefes Arch Clin Exp Ophthalmol 2021 Feb;259(2):369-378.PMID:32852613DOI:10.1007/s00417-020-04899-y.
Purpose: To evaluate the effects of oral Emixustat hydrochloride on pro-angiogenic and inflammatory cytokines in the aqueous humor, as well as other ophthalmic parameters, in subjects with proliferative diabetic retinopathy (PDR). Methods: Twenty-three patients with PDR, with or without diabetic macular edema (DME), were assigned to emixustat or placebo in daily oral doses ranging from 5 to 40 mg over a step-up titration period, for 84 days. The main outcome measures included levels of IL-1β, IL-6, IL-8, TGFβ-1, and VEGF in the aqueous humor. Results: Seven of 12 subjects (58%) who were randomized to emixustat and 11 of 12 subjects (92%) who were randomized to placebo completed the study. No statistically significant differences between treatment groups were observed for changes in any of the aqueous humor cytokines tested. However, median VEGF levels were slightly reduced in the emixustat but not the placebo group (- 70.0 pg/mL versus + 42.7 pg/mL, or - 11.8% versus + 6.7%). In a post hoc analysis of all subjects (with or without DME), statistically significant differences between treatment arms in mean changes from baseline in central subfield thickness (CST; emixustat - 11.9 μm, placebo + 36.2 μm; P = 0.076) and total macular volume (TMV; emixustat - 0.13 mm3, placebo + 0.23 mm3; P = 0.026) were observed, both favoring emixustat. Emixustat's safety profile was consistent with prior studies (i.e., the adverse events of delayed dark adaptation and visual impairment were more common in subjects treated with emixustat). Conclusion: Although this pilot study did not demonstrate statistically significant differences in changes in aqueous humor cytokine levels between the emixustat and placebo groups, VEGF levels were slightly reduced in the emixustat but not in the placebo group. In addition, statistically significant differences favoring the emixustat group were observed in CST and TMV among all subjects. These data warrant further investigation of emixustat's potential therapeutic effects in diabetic retinopathy. Trial registration: ClinicalTrials.gov identifier: NCT02753400 (April 2016).
Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity
PLoS One 2015 May 13;10(5):e0124940.PMID:25970164DOI:10.1371/journal.pone.0124940.
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.
Randomised study evaluating the pharmacodynamics of Emixustat hydrochloride in subjects with macular atrophy secondary to Stargardt disease
Br J Ophthalmol 2022 Mar;106(3):403-408.PMID:33214244DOI:10.1136/bjophthalmol-2020-317712.
Background/aims: Stargardt disease is a rare, inherited, degenerative disease of the retina that is the most common type of hereditary macular dystrophy. Currently, no approved treatments for the disease exist. The purpose of this study was to characterise the pharmacodynamics of emixustat, an orally available small molecule that targets the retinal pigment epithelium-specific 65 kDa protein (RPE65), in subjects with macular atrophy secondary to Stargardt disease. Methods: In this multicentre study conducted at six study sites in the USA, 23 subjects with macular atrophy secondary to Stargardt disease were randomised to one of three doses of daily emixustat (2.5 mg, 5 mg or 10 mg) and treated for 1 month. The primary outcome was the suppression of the rod b-wave recovery rate on electroretinography after photobleaching, which is an indirect measure of RPE65 inhibition. Results: Subjects who received 10 mg emixustat showed near-complete suppression of the rod b-wave amplitude recovery rate postphotobleaching (mean=91.86%, median=96.69%), whereas those who received 5 mg showed moderate suppression (mean=52.2%, median=68.0%). No effect was observed for subjects who received 2.5 mg emixustat (mean=-3.31%, median=-12.23%). The adverse event profile was consistent with prior studies in other patient populations and consisted primarily of ocular adverse events likely related to RPE65 inhibition. Conclusion: This study demonstrated dose-dependent suppression of rod b-wave amplitude recovery postphotobleaching, confirming emixustat's biological activity in patients with Stargardt disease. These findings informed dose selection for a 24-month phase 3 trial (SeaSTAR Study) that is now comparing emixustat to placebo in the treatment of Stargardt disease-associated macular atrophy.