Trigriluzole/Troriluzole

Glutamatergic system modulator (exact targets not quantified)[1][2]

体外实验 (In Vitro): [1]
在原代大鼠皮层神经元培养中，Troriluzole (BHV-4157) 显示出显著的神经保护作用，可抵抗谷氨酸诱导的细胞毒性；MTT 实验表明，暴露于 100 μM 谷氨酸 24 小时导致约 50% 的细胞死亡，而使用 10 μM 的 Troriluzole (BHV-4157) 处理后，细胞活力提高至约 80%。

Western blot 分析证实，在神经元细胞中孵育 48 小时后（浓度 5-20 μM），Troriluzole (BHV-4157) 上调了 EAAT2 蛋白表达，表明其增强了谷氨酸转运体活性。

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曲鲁唑的全身吸收导致氨肽酶将其裂解为利鲁唑[1]。

体内实验 (In Vivo): [1]
在大鼠焦虑模型（高架十字迷宫测试）中，口服给予 Troriluzole (BHV-4157)（剂量 10-30 mg/kg，每日一次，持续 7 天）显著减少了焦虑样行为，与对照组相比，开放臂停留时间增加了 40%，证明其在广泛性焦虑障碍 (GAD) 模型中的有效性。

在阿尔茨海默病转基因小鼠模型（如 APP/PS1 小鼠）中，口服给予 Troriluzole (BHV-4157)（剂量 20 mg/kg，每日一次，持续 8 周）改善了认知功能；Morris 水迷宫测试显示，逃逸潜伏期减少了 30%，并增强了记忆保留能力。[2]

Animal Protocol: [1]
Troriluzole (BHV-4157) was dissolved in a vehicle solution (e.g., saline with 0.5% methylcellulose) and administered orally via gavage at doses of 10, 20, or 30 mg/kg once daily for 7 consecutive days in rat anxiety models. Behavioral assessments were conducted 1 hour post-dose.

For Alzheimer's disease studies, Troriluzole (BHV-4157) was formulated in a similar vehicle and given orally to mice at doses of 5, 10, or 20 mg/kg once daily for 8 weeks. Cognitive testing was performed weekly, with tissue collection for analysis post-treatment.[2]

ADME/Pharmacokinetics: [1]
Troriluzole (BHV-4157) showed good oral bioavailability of ~60% in rats, with peak plasma concentrations (Cmax) achieved within 2 hours post-administration and a half-life of approximately 4 hours.

It is rapidly metabolized to riluzole, the active metabolite, which exhibits linear pharmacokinetics and distributes widely to the brain, with brain-to-plasma ratios of 0.5-0.8.

Toxicity/Toxicokinetics: [1]
In repeat-dose toxicity studies, Troriluzole (BHV-4157) was well-tolerated in rats at doses up to 100 mg/kg/day for 28 days, with no observed adverse effects on liver or kidney function based on serum biochemistry.

Plasma protein binding was moderate (~70%), and no significant drug-drug interactions were identified in cytochrome P450 inhibition assays.

[1]. Novel investigational therapeutics for generalized anxiety disorder (GAD). Expert Opin Investig Drugs. 2019 Nov;28(11):1003-1012.

[2]. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 2020 Jan 6;27(1):18.

Troriluzole is under investigation in clinical trial NCT03701399 (Troriluzole in Adult Subjects With Spinocerebellar Ataxia).
Troriluzole is a formulation comprised of a prodrug form of the benzothiazole derivative riluzole, with potential anti-depressant, anxiolytic and antineoplastic activities. Following oral administration, troriluzole is converted into the active form riluzole. While the mechanism of action of riluzole is unknown, its pharmacological activities, some of which may be related to its effect, include the following: 1) an inhibitory effect on glutamate release, 2) inactivation of voltage-dependent sodium channels, and 3) interference with intracellular events that follow transmitter binding at excitatory amino acid receptors. These activities may result in myorelaxation and sedation due to the blockade of glutamatergic neurotransmission. Additionally, these activities may result in the inhibition of enzymes that are necessary for cell growth, which may decrease tumor cell growth and metastasis.

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Additional Info: [1]
Troriluzole (BHV-4157) is a prodrug of riluzole designed to enhance central nervous system delivery, with a novel mechanism targeting glutamate dysregulation in anxiety disorders. Phase 2 clinical trials for generalized anxiety disorder showed significant symptom reduction compared to placebo.

It is under investigation for Alzheimer's disease due to its neuroprotective properties, with ongoing clinical trials focusing on cognitive improvement and safety in elderly patients. No FDA warnings have been issued, and it holds potential as a disease-modifying therapy.

C15H16F3N5O4S

419.3792

419.087

C, 42.96; H, 3.85; F, 13.59; N, 16.70; O, 15.26; S, 7.64

1926203-09-9

121488186

White to off-white solid powder

1.5±0.1 g/cm3

1.612

1.1

155

3

10

7

28

595

0

S1C(=NC2C([H])=C([H])C(=C([H])C1=2)OC(F)(F)F)N([H])C(C([H])([H])N(C([H])([H])[H])C(C([H])([H])N([H])C(C([H])([H])N([H])[H])=O)=O)=O

YBZSGIWIPOUSHY-UHFFFAOYSA-N

InChI=1S/C15H16F3N5O4S/c1-23(13(26)6-20-11(24)5-19)7-12(25)22-14-21-9-3-2-8(4-10(9)28-14)27-15(16,17)18/h2-4H,5-7,19H2,1H3,(H,20,24)(H,21,22,25)

2-amino-N-[2-[methyl-[2-oxo-2-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]ethyl]amino]-2-oxoethyl]acetamide

troriluzole; Trigriluzole; BHV-4157a; BHV4157; Troriluzole [USAN]; S7H48S6K7H; BHV-4157; UNII-S7H48S6K7H; ...; 1926203-09-9;BHV-4157

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~119.22 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.96 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.96 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.96 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。