Troriluzole
(Synonyms: BHV-4157) 目录号 : GC67783Troriluzole 是 Riluzole 的第三代三肽前药，是一种具有口服活性谷氨酸调节剂。Troriluzole 可以降低突触谷氨酸水平并增加突触谷氨酸的吸收。Troriluzole 具有用于阿尔茨海默病和广泛性焦虑症 (GAD) 的潜力。
Cas No.:1926203-09-9
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Troriluzole, a third-generation, tripeptide prodrug of Riluzole , is an orally active glutamate modulator. Troriluzole reduces synaptic glutamate level and increases the synaptic glutamate absorption. Troriluzole has the potential for Alzheimer disease and generalized anxiety disorder (GAD)[1][2].
Troriluzole is absorbed systemically and cleaves into riluzole by aminopeptidases[1].
[1]. Schanzer B, et al. Novel investigational therapeutics for generalized anxiety disorder (GAD). Expert Opin Investig Drugs. 2019 Nov;28(11):1003-1012.
[2]. Huang LK, et al. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 2020 Jan 6;27(1):18.
| Cas No. | 1926203-09-9 | SDF | Download SDF |
| 别名 | BHV-4157 | ||
| 分子式 | C15H16F3N5O4S | 分子量 | 419.38 |
| 溶解度 | DMSO : 50 mg/mL (119.22 mM; Need ultrasonic) | 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。 |
||
| 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 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.3845 mL | 11.9224 mL | 23.8447 mL |
| 5 mM | 0.4769 mL | 2.3845 mL | 4.7689 mL |
| 10 mM | 0.2384 mL | 1.1922 mL | 2.3845 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。
Investigational and Experimental Drugs to Treat Obsessive-Compulsive Disorder
J Exp Pharmacol 2021 Jan 5;12:695-706.PMID:33447096DOI:10.2147/JEP.S255375.
Treatment-resistance is a frequent condition for obsessive-compulsive disorder (OCD). Over the past decades, a lot of effort has been made to address this issue, and several augmentation strategies of serotonergic drugs have been investigated. Antidopaminergic drugs are considered the first choice as augmentation strategy for treatment-resistant OCD patients, but they seem to work only for a subset of patients, and none of them have been officially approved for OCD. Recently, the role of glutamate and inflammation in OCD pathophysiology clearly emerged, and this has led to several investigations on glutamatergic and anti-inflammatory agents. Results seem promising but still inconclusive. Probiotic interventions (considered to modulate the immune systems and the brain activity) are gaining attention in several psychiatric fields but are still at their early stages in the OCD field. Research on new treatment approaches for OCD is moving forward, and more than one hundred interventional trials are ongoing around the world. While the vast majority of these trials involve neuromodulation and psychotherapeutic approaches, only a small proportion (around 20%) involve the investigation of new pharmacological approaches (tolcapone, nabilone, psilocybin, Troriluzole, nitrous oxide, rituximab, naproxen, and immunoglobulins). Here, we provide a comprehensive review of investigational and experimental drugs to treat OCD.
A phase Ib dose-escalation study of Troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors
Eur J Med Res 2022 Jul 2;27(1):107.PMID:35780243DOI:10.1186/s40001-022-00732-w.
Background: Glutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug Troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors. Methods: Patients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of Troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of Troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy. Results: We enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received Troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug Troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested. Conclusion: The combination of Troriluzole and nivolumab was safe and well-tolerated. The MTD of Troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors. Trial Registration ClinicalTrials.gov Identifier NCT03229278.
Troriluzole inhibits methamphetamine place preference in rats and normalizes methamphetamine-evoked glutamate carboxypeptidase II (GCPII) protein levels in the mesolimbic pathway
Drug Alcohol Depend 2023 Jan 1;242:109719.PMID:PMC9850846DOI:10.1016/j.drugalcdep.2022.109719.
Riluzole, approved to manage amyotrophic lateral sclerosis, is mechanistically unique among glutamate-based therapeutics because it reduces glutamate transmission through a dual mechanism (i.e., reduces glutamate release and enhances glutamate reuptake). The profile of riluzole is favorable for normalizing glutamatergic dysregulation that perpetuates methamphetamine (METH) dependence, but pharmacokinetic and metabolic liabilities hinder repurposing. To mitigate these limitations, we synthesized Troriluzole (TRLZ), a third-generation prodrug of riluzole, and tested the hypothesis that TRLZ inhibits METH hyperlocomotion and conditioned place preference (CPP) and normalizes METH-induced changes in mesolimbic glutamate biomarkers. TRLZ (8, 16 mg/kg) reduced hyperlocomotion caused by METH (1 mg/kg) without affecting spontaneous activity. TRLZ (1, 4, 8, 16 mg/kg) administered during METH conditioning (0.5 mg/kg x 4 d) inhibited development of METH place preference, and TRLZ (16 mg/kg) administered after METH conditioning reduced expression of CPP. In rats with established METH place preference, TRLZ (16 mg/kg) accelerated extinction of CPP. In cellular studies, chronic METH enhanced mRNA levels of glutamate carboxypeptidase II (GCPII) in the ventral tegmental area (VTA) and prefrontal cortex (PFC). Repeated METH also caused enhancement of GCPII protein levels in the VTA that was prevented by TRLZ (16 mg/kg). TRLZ (16 mg/kg) administered during chronic METH did not affect brain or plasma levels of METH. These results indicate that TRLZ, already in clinical trials for cerebellar ataxia, reduces development, expression and maintenance of METH CPP. Moreover, normalization of METH-induced GCPII levels in mesolimbic substrates by TRLZ points toward studying GCPII as a therapeutic target of TRLZ.
A SPONTANEOUS MELANOMA MOUSE MODEL APPLICABLE FOR A LONGITUDINAL CHEMOTHERAPY AND IMMUNOTHERAPY STUDY
J Invest Dermatol 2023 Mar 28;S0022-202X(23)01951-6.PMID:36997110DOI:10.1016/j.jid.2023.03.1664.
Mouse models that reflect human disorders provide invaluable tools towards the translation of basic science discoveries to clinical therapies. However, many of these in vivo therapeutic studies are short-term and do not accurately mimic patient conditions. In this study, we utilized a fully immuno-competent, transgenic mouse model, TGS, in which the spontaneous development of metastatic melanoma is driven by the ectopic expression of a normal neuronal receptor, metabotropic glutamate receptor 1 (mGluR1), as a model to assess longitudinal treatment response (up to 8 months) with an inhibitor of glutamatergic signaling, Troriluzole, a prodrug of riluzole, plus an antibody against programmed cell death protein-1 (PD-1), an immune-checkpoint inhibitor. Our results reveal a sex-biased treatment response that led to an improved survival in Troriluzole and/or anti-PD-1 treated male mice that correlated with differential CD8+ T-cells and CD11b+ myeloid cell populations in the tumor-stromal interface, supporting the notion that this model is a responsive and tractable system for evaluating therapeutic regimens for melanoma in an immuno-competent setting.
T2 Protect AD: Achieving a rapid recruitment timeline in a multisite clinical trial for individuals with mild to moderate Alzheimer's disease
Alzheimers Dement (N Y) 2022 Mar 14;8(1):e12265.PMID:35310528DOI:10.1002/trc2.12265.
Introduction: The reporting of approaches facilitating the most efficient and timely recruitment of Alzheimer's disease (AD) patients into pharmacologic trials is fundamental to much-needed therapeutic progress. Methods: T2 Protect AD (T2), a phase 2 randomized placebo-controlled trial of Troriluzole in mild to moderate AD, used multiple recruitment strategies. Results: T2 exceeded its recruitment target, enrolling 350 participants between July 2018 and December 2019 (randomization rate: 0.87 randomizations/site/month, or 3-fold greater than recent trials of mild to moderate AD). The vast majority (98%) of participants were enrolled during a 10-month window of intense promotion in news media, TV and radio advertisements, and social media. The distribution of primary recruitment sources included: existing patient lists at participating sites (72.3%), news media (12.3%), physician referral (6.0%), word of mouth (3.1%), and paid advertising (2.9%). Discussion: The rapid recruitment of participants with mild to moderate AD was achieved through a range of approaches with varying success.