CT1812
(Synonyms: Sigma-2 receptor antagonist 1) 目录号 : GC65450
CT1812 (Sigma-2 receptor antagonist 1) 是 sigma-2 (σ-2) 受体拮抗剂。
Cas No.:1802632-22-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >97.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
CT1812 (Sigma-2 receptor antagonist 1) is a sigma-2 (σ-2) receptor antagonist.
| Cas No. | 1802632-22-9 | SDF | Download SDF |
| 别名 | Sigma-2 receptor antagonist 1 | ||
| 分子式 | C24H33NO4S | 分子量 | 431.59 |
| 溶解度 | DMSO : 250 mg/mL (579.25 mM; Need ultrasonic) | 储存条件 | 4°C, protect from light |
| 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 | 2.317 mL | 11.5851 mL | 23.1701 mL |
| 5 mM | 0.4634 mL | 2.317 mL | 4.634 mL |
| 10 mM | 0.2317 mL | 1.1585 mL | 2.317 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；
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。
Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification
Alzheimers Dement 2021 Aug;17(8):1365-1382.PMID:33559354DOI:10.1002/alz.12302.
Introduction: Amyloid beta (Aβ) oligomers are one of the most toxic structural forms of the Aβ protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients' brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block Aβ oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on Aβ oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). Methods: Experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APPSwe /PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer-induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPPSwe/Lnd+ and wild-type littermates. A multicenter, double-blind, placebo-controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini-Mental State Examination 18-26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme-linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo-treated dosing groups. Results: CT1812 significantly and dose-dependently displaced Aβ oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aβ oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. Discussion: These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and Aβ oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812.
The Allosteric Antagonist of the Sigma-2 Receptors-Elayta (CT1812) as a Therapeutic Candidate for Mild to Moderate Alzheimer's Disease: A Scoping Systematic Review
Life (Basel) 2022 Dec 20;13(1):1.PMID:36675950DOI:10.3390/life13010001.
Nearly 35 million people worldwide live with Alzheimer's disease (AD). The prevalence of the disease is expected to rise two-fold by 2050. With only symptomatic treatment options available, it is essential to understand the developments and existing evidence that aims to target brain pathology and dementia outcomes. This scoping systematic review aimed to collate existing evidence of CT1812 for use in patients with AD and summarize the methodologies of ongoing trials. Adhering to PRISMA Statement 2020 guidelines, PubMed/MEDLINE, Embase, Cochrane, and ClinicalTrials.gov were systematically searched through up to 15 November 2022 by applying the following keywords: CT1812, Alzheimer's disease, dementia, and/or sigma-2 receptor. Three completed clinical trials were included along with three ongoing records of clinical trials. The three completed trials were in Phases I and II of testing. The sample size across all three trials was 135. CT1812 reached endpoints across the trials and obtained a maximum concentration in the cerebrospinal fluid with 97-98% receptor occupancy. The findings of this systematic review must be used with caution as the results, while mostly favorable so far, must be replicated in higher-powered, placebo-controlled Phase II-III trials.
Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer's Disease
ACS Med Chem Lett 2021 Aug 9;12(9):1389-1395.PMID:34531947DOI:10.1021/acsmedchemlett.1c00048.
An unbiased phenotypic neuronal assay was developed to measure the synaptotoxic effects of soluble Aβ oligomers. A collection of CNS druglike small molecules prepared by conditioned extraction was screened. Compounds that prevented and reversed synaptotoxic effects of Aβ oligomers in neurons were discovered to bind to the sigma-2 receptor complex. Select development compounds displaced receptor-bound Aβ oligomers, rescued synapses, and restored cognitive function in transgenic hAPP Swe/Ldn mice. Our first-in-class orally administered small molecule investigational drug 7 (CT1812) has been advanced to Phase II clinical studies for Alzheimer's disease.
Many or too many progesterone membrane receptors? Clinical implications
Trends Endocrinol Metab 2022 Dec;33(12):850-868.PMID:36384863DOI:10.1016/j.tem.2022.10.001.
Several receptors for nongenomically initiated actions of progesterone (P4) exist, namely membrane-associated P4 receptors (MAPRs), membrane progestin receptors (mPRs), receptors for neurosteroids [GABAA receptor (GABAAR), NMDA receptor, sigma-1 and -2 receptors (S1R/S2R)], the classical genomic P4 receptor (PGR), and α/β hydrolase domain-containing protein 2 (ABHD2). Two drugs related to this field have been approved: brexanolone (Zulresso™) for the treatment of postpartum depression, and ganaxolone (Ztalmy™) for the treatment of CDKL5 deficiency disorder. Both are derivatives of P4 and target the GABAAR. Several other indications are in clinical testing. CT1812 (Elayta™) is also being tested for the treatment of Alzheimer's disease (AD) in Phase 2 clinical trials, targeting the P4 receptor membrane component 1 (PGRMC1)/S2R complex. In this Review, we highlight emerging knowledge on the mechanisms of nongenomically initiated actions of P4 and its derivatives.
A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer's disease
Alzheimers Dement (N Y) 2019 Jan 23;5:20-26.PMID:30723776DOI:10.1016/j.trci.2018.11.001.
Background: Elayta (CT1812) is a novel allosteric antagonist of the sigma-2 receptor complex that prevents and displaces binding of Aβ oligomers to neurons. By stopping a key initiating event in Alzheimer's disease, this first-in-class drug candidate mitigates downstream synaptotoxicity and restores cognitive function in aged transgenic mouse models of Alzheimer's disease. Methods: A phase 1, two-part single and multiple ascending dose study was conducted in 7 and 4 cohorts of healthy human subjects, respectively. In part A, healthy, young subjects (<65 years old) received CT1812 doses ranging from 10 to 1120 mg (6:2 active to placebo [A:P] per cohort). In part B, subjects were administered 280, 560, and 840 mg once daily for 14 days (8:2 A:P per cohort). An elderly cohort, aged 65-75 years, was dosed at 560 mg once daily for 14 days (7:2 A:P). Serum concentrations of CT1812 in part B were measured on day 3 and 14 and cerebrospinal fluid concentrations on day 7 or 9. Cognitive testing was performed in the healthy elderly cohort at baseline and at day 14 of treatment. Results: Treatment with CT1812 was well tolerated in all cohorts. Adverse events were mild to moderate in severity and included headache and GI tract symptoms. Plasma concentrations of drug were dose proportional across two orders of magnitude with minimal accumulation over 14 days. Cognitive scores in the healthy elderly cohort were similar before and after treatment. Conclusions: CT1812 was well tolerated with single dose administration up to 1120 mg and with multiple dose administration up to 840 mg and 560 mg in healthy young and healthy elderly subjects, respectively. CT1812 is currently being studied in early phase 2 trials in patients with Alzheimer's disease.