Foliglurax
(Synonyms: PXT002331) 目录号 : GC36064
Foliglurax (PXT002331) 是一种可渗透脑的，有效的选择性代谢型谷氨酸受体 4 正变构调节剂 (mGluR4 PAM)，EC50 为 79 nM。抗帕金森病。
Cas No.:1883329-51-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Foliglurax (PXT002331) is a highly selective and potent, brain-penetrant metabotropic glutamate receptor 4 positive allosteric modulator (mGluR4 PAM) with an EC50 of 79 nM[1]. Antiparkinsonian effect[1]. mGlu4|79 nM (EC50)
Foliglurax, a highly selective and potent mGlu4 receptor PAM with a marked brain-penetrance feature, might revolutionize the field of mGlu4 receptor drug targeting in CNS disorders[2].
[1]. Charvin D, et al. Discovery, Structure-Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4. J Med Chem. 2017 Oct 26;60(20):8515-8537. [2]. Volpi C, et al. Opportunities and challenges in drug discovery targeting metabotropic glutamate receptor 4. Expert Opin Drug Discov. 2018 May;13(5):411-423.
| Cas No. | 1883329-51-8 | SDF | |
| 别名 | PXT002331 | ||
| Canonical SMILES | O/N=C1C=C(C2=CC3=C(C=CS3)C=N2)OC4=CC=C(CCCN5CCOCC5)C=C\14 | ||
| 分子式 | C23H23N3O3S | 分子量 | 421.51 |
| 溶解度 | DMSO: 5.2 mg/mL (12.34 mM and warming) | 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 | 2.3724 mL | 11.8621 mL | 23.7242 mL |
| 5 mM | 0.4745 mL | 2.3724 mL | 4.7448 mL |
| 10 mM | 0.2372 mL | 1.1862 mL | 2.3724 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。
A case study of Foliglurax, the first clinical mGluR4 PAM for symptomatic treatment of Parkinson's disease: translational gaps or a failing industry innovation model?
Expert Opin Investig Drugs 2020 Dec;29(12):1323-1338.PMID:33074728DOI:10.1080/13543784.2020.1839047.
Introduction: Approximately 40% of Parkinson's disease (PD) patients that take mostly dopamine receptor agonists for motor fluctuations, experience the return of symptoms between regular doses. This is a phenomenon known as 'OFF periods.' Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) are a promising non-dopaminergic mechanism with potential to address the unmet need of patients suffering from OFF periods. Foliglurax is the first mGluR4 PAM that has advanced into clinical testing in PD patients. Areas covered: We summarize the chemistry, pharmacokinetics, and preclinical pharmacology of Foliglurax. Translational PET imaging studies, clinical efficacy data, and a competitive landscape analysis of available therapies are presented to the readers. In this Perspective article, Foliglurax is used as a case study to illustrate the inherent R&D challenges that companies face when developing drugs. These challenges include the delivery of drugs acting through novel mechanisms, long-term scientific investment, and commercial success and shorter-term positive financial returns. Expert opinion: Failure to meet the primary and secondary endpoints in a Phase 2 study led Lundbeck to discontinue the development of Foliglurax. Understanding the evidence supporting compound progression into Phase 2 will enable the proper assessment of the therapeutic potential of mGluR4 PAMs.
A Randomized, Double-Blind, Controlled Phase II Study of Foliglurax in Parkinson's Disease
Mov Disord 2022 May;37(5):1088-1093.PMID:35218231DOI:10.1002/mds.28970.
Background: Agents targeting the metabotropic glutamate receptor 4 have emerged as a potentially attractive new class of drugs for the treatment of Parkinson's disease (PD). Objective: The objective of this study was to evaluate the efficacy and safety of Foliglurax in reducing off time and dyskinesia in patients with PD. Methods: This was a 28-day, multicenter, randomized, placebo-controlled, double-blind clinical trial of Foliglurax 10 and 30 mg as adjunct to levodopa in 157 randomly assigned patients with PD and motor complications. Results: Although dose-dependent decreases in daily awake off time were apparent following treatment with Foliglurax, the change from baseline to day 28 in off time (primary endpoint) and dyskinesia (secondary endpoint) did not improve significantly compared with placebo for either Foliglurax dose. Treatment with Foliglurax was generally safe, and there were no relevant safety signals. Conclusions: There was no evidence in this study that Foliglurax has efficacy in improving levodopa-induced motor complications in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Foliglurax, a positive allosteric modulator of the metabotrophic glutamate receptor 4, protects dopaminergic neurons in MPTP-lesioned male mice
Brain Res 2023 Mar 25;1809:148349.PMID:36972837DOI:10.1016/j.brainres.2023.148349.
Overactivity of the corticostriatal glutamatergic pathway is documented in Parkinson's disease (PD) and stimulation of presynaptic metabotropic glutamate (mGlu) receptors 4 on these striatal afferents inhibits glutamate release normalizing neuronal activity in the basal ganglia. Moreover, mGlu4 receptors are also expressed in glial cells and are able to modulate glial function making this receptor a potential target for neuroprotection. Hence, we investigated whether Foliglurax, a positive allosteric modulator of mGlu4 receptors with high brain exposure after oral administration, has neuroprotective effects in MPTP mice to model early PD. Male mice were treated daily from day 1 to 10 with 1, 3 or 10 mg/kg of Foliglurax and administered MPTP on the 5th day then euthanized on the 11th day. Dopamine neuron integrity was assessed with measures of striatal dopamine and its metabolites levels, striatal and nigral dopamine transporter (DAT) binding and inflammation with markers of striatal astrocytes (GFAP) and microglia (Iba1). MPTP lesion produced a decrease in dopamine, its metabolites and striatal DAT specific binding that was prevented by treatment with 3 mg/kg of Foliglurax, whereas 1 and 10 mg/kg had no beneficial effect. MPTP mice had increased levels of GFAP; Foliglurax treatment (3 mg/kg) prevented this increase. Iba1 levels were unchanged in MPTP mice compared to control mice. There was a negative correlation between dopamine content and GFAP levels. Our results show that positive allosteric modulation of mGlu4 receptors with Foliglurax provided neuroprotective effects in the MPTP mouse model of PD.
Clinical investigations of compounds targeting metabotropic glutamate receptors
Pharmacol Biochem Behav 2022 Sep;219:173446.PMID:35987339DOI:10.1016/j.pbb.2022.173446.
Pharmacological modulation of glutamate has long been considered to be of immense therapeutic utility. The metabotropic glutamate receptors (mGluRs) are potential targets for safely altering glutamate-driven excitation. Data support the potential therapeutic use of mGluR modulators in the treatment of anxiety, depression, schizophrenia, and other psychiatric disorders, pain, epilepsy, as well as neurodegenerative and neurodevelopmental disorders. For each of the three mGluR groups, compounds have been constructed that produce either potentiation or functional blockade. PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059. Efficacy with mGlu5R antagonists has been reported in trials with patients with gastroesophageal reflux disease; data from patients with Parkinson's disease or Fragile X syndrome have not been as robust as hoped. Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression. The Group III mGluRs are the least developed of the mGluR receptor targets. The mGlu4R potentiator, Foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders.
Opportunities and challenges in drug discovery targeting metabotropic glutamate receptor 4
Expert Opin Drug Discov 2018 May;13(5):411-423.PMID:29486616DOI:10.1080/17460441.2018.1443076.
Until recently, metabotropic glutamate receptor 4 (mGlu4) has not received adequate attention in terms of drug targeting when compared to other members of the same mGlu receptor family, possibly because of the difficulties encountered in developing highly selective, either orthosteric or allosteric, ligands for this receptor. Areas covered: This review gives to discussion to the past and recent advances (between 2012-2017) in targeting the mGlu4 receptor for the treatment of disorders of the central nervous system (CNS) as well as immunological (neuroinflammation) and metabolic diseases (diabetes). Chemical structures, properties, and pharmacological properties discussed herein were retrieved from the scientific literature databases, PubMed and Google Scholar. Expert opinion: The fertile field of mGlu receptor positive allosteric modulators (PAMs) has recently led to the discovery of Foliglurax, a highly selective mGlu4 receptor PAM with optimal bioavailability after oral administration and excellent brain distribution. However, further elucidation of the biological properties of the mGlu4 receptor, including expression and its signalling profile in distinct tissues and cells are still awaited in order to establish the mGlu4 receptor as a definite drug target in several CNS and non-CNS diseases.