LY2140023
(Synonyms: LY2140023) 目录号 : GC61016
LY2140023 (LY2140023) 是选择性 mGlu2/3 受体激动剂 LY404039 的口服活性蛋氨酸前药。
Cas No.:635318-55-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
LY2140023 is an orally active prodrug of LY404039. LY404039 is a selective metabotropic glutamate 2/3 receptor agonist. LY2140023 has the potential for schizophrenia[1].
LY2140023 (orally; 3, 10, and 300 mg/kg; once daily for 7 days) dose-dependent increases the levels of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)[1]. Animal Model: Male Fischer rats (approximately 250 g)[1]
[1]. Lowe S, et al. Effects of a novel mGlu?/? receptor agonist prodrug, LY2140023 monohydrate, on central monoamine turnover as determined in human and rat cerebrospinal fluid. Psychopharmacology (Berl). 2012 Feb;219(4):959-70.
| Cas No. | 635318-55-7 | SDF | |
| 别名 | LY2140023 | ||
| Canonical SMILES | O=C([C@]1(NC([C@@H](N)CCSC)=O)CS([C@@]2([H])[C@H](C(O)=O)[C@@]12[H])(=O)=O)O | ||
| 分子式 | C12H18N2O7S2 | 分子量 | 366.41 |
| 溶解度 | DMSO: 13.33 mg/mL (36.38 mM); Water: < 0.1 mg/mL (insoluble) | 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 | 2.7292 mL | 13.6459 mL | 27.2918 mL |
| 5 mM | 0.5458 mL | 2.7292 mL | 5.4584 mL |
| 10 mM | 0.2729 mL | 1.3646 mL | 2.7292 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。
Role of calcium, glutamate and NMDA in major depression and therapeutic application
Prog Neuropsychopharmacol Biol Psychiatry 2016 Jan 4;64:325-33.PMID:25747801DOI:10.1016/j.pnpbp.2015.02.015.
Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-D-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, D-cycloserine, D-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-aminocyclopropanecarboxylic acid, all of which target this system, have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression.
Pharmacogenetic analysis of the mGlu2/3 agonist LY2140023 monohydrate in the treatment of schizophrenia
Pharmacogenomics J 2012 Jun;12(3):246-54.PMID:21173788DOI:10.1038/tpj.2010.90.
The goal of this study was to identify genetic markers associated with LY2140023 monohydrate response in patients with schizophrenia. Variants in eight candidate genes related to the mechanism of action of LY2140023 or olanzapine were investigated in a genetic cohort collected from two clinical trials. Results from this genetic analysis indicate that 23 single nucleotide polymorphisms (SNPs) were associated with a change in Positive and Negative Syndrome Scale total score in response to LY2140023 at 28 days (P<0.01; false discovery rate <0.2). Sixteen of these SNPs were located in the serotonin 2A receptor (HTR2A). Bioinformatic analyses identified a putative antisense nested gene in intron 2 of HTR2A in the region of the genetic markers associated with LY2140023 response. These data suggest a genetic association exists between SNPs in several genes, such as HTR2A, and response to LY2140023 treatment. Additional clinical trials are needed to establish replication of these results.
A Double-Blind, Placebo-Controlled Comparator Study of LY2140023 monohydrate in patients with schizophrenia
BMC Psychiatry 2014 Dec 10;14:351.PMID:25539791DOI:10.1186/s12888-014-0351-3.
Background: Pomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia. Methods: Enrolled adult patients (ages 18-65) with schizophrenia who had experienced an exacerbation of symptoms within 2 weeks prior to study entry. Patients (N = 1013) were randomized 2:2:2:1 to treatment with placebo, LY40 mg twice daily (BID), LY80 mg BID, or risperidone (RIS) 2 mg BID for 6 weeks after a one-week blinded placebo lead-in. The primary outcome assessed change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in an overall schizophrenia population and a predefined subpopulation which excluded non-Hispanic white patients with the A/A genotype at the HTR2A SNP rs7330461. Results: Neither LY2140023 dose showed significant improvement compared to placebo on PANSS total in either population (1-sided p-value [significance level], overall: LY40, p = .154 [0.01]; LY80, p = .698 [0.01], subpopulation: LY40, p = .033 [0.0025]; LY80, p = .659 [0.0025], MMRM analysis). RIS statistically separated from placebo in both populations (p < .001 [0.05]). There were no statistically significant differences in the incidence of serious adverse events, and no seizures on LY2140023. Conclusion: LY2140023 treatment did not demonstrate efficacy in populations studied. Overall, LY2140023 treatment was generally well tolerated with no new adverse safety findings compared to previous trials. Further understanding of the role of glutamate as a therapeutic target in schizophrenia is needed. Clinical trials registration: A Phase 2, Multicenter, Double-Blind, Placebo-Controlled Comparator Study of 2 Doses of LY2140023 Versus Placebo in Patients With DSM-IV-TR SchizophreniaClinicalTrials.gov identifier: NCT01086748.
Effects of a novel mGlu₂/₃ receptor agonist prodrug, LY2140023 monohydrate, on central monoamine turnover as determined in human and rat cerebrospinal fluid
Psychopharmacology (Berl) 2012 Feb;219(4):959-70.PMID:21847569DOI:10.1007/s00213-011-2427-9.
Rationale: Accumulating evidence suggests that the primary symptoms of schizophrenia may be associated with altered central glutamate transmission. LY2140023 monohydrate is the methionine prodrug of the selective mGlu(2/3) receptor agonist LY404039 and is currently being assessed for the treatment of schizophrenia. Objective: The objective of this study was to evaluate the central pharmacological activity of LY2140023 monohydrate in preclinical and clinical studies. Methods: Effects on neurotransmitter/metabolite concentrations were assessed in male rats following single oral doses of LY2140023 monohydrate (microdiasylates from the prefrontal cortex), single intraperitoneal injection of LY404039 [cerebrospinal fluid (CSF)], or LY2140023 monohydrate dosed once daily for 7 days (CSF). A clinical study in 16 healthy subjects assessed the effects of LY2140023 monohydrate 40 mg orally twice daily for 14 days in lumbar CSF. Results: Rat studies: Acute dosing with LY2140023 monohydrate resulted in significant dose-dependent increases in extracellular concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), but not 5-hydroxyindoleacetic acid (5-HIAA), in the prefrontal cortex. LY2140023 monohydrate dosing for 7 days elevated the concentrations of HVA in CSF, while acutely dosed LY404039 increased the concentrations of DOPAC, HVA, and methoxy-hydroxyphenylglycol (MHPG), but not 5-HIAA. Clinical study: Significant increases were seen for DOPAC, HVA, 5-HIAA, and MHPG in the CSF of subjects receiving LY2140023 monohydrate, but not placebo. Conclusions: LY2140023 monohydrate and/or LY404039 dosing potently affected dopamine turnover and also significantly affected serotonin turnover in the human and rat central nervous systems. The measurement of biogenic amine metabolites such as DOPAC and HVA may serve as useful biomarkers of LY2140023 monohydrate and/or LY404039 central pharmacodynamic activity.
A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia
J Clin Psychopharmacol 2011 Jun;31(3):349-55.PMID:21508856DOI:10.1097/JCP.0b013e318218dcd5.
The primary objective of this study was to test the hypothesis that 1 or more dose levels of LY2140023 monohydrate, an oral prodrug of the potent metabotropic glutamate (mGlu) 2/3 receptor agonist LY404039, given to patients with schizophrenia for 4 weeks would demonstrate significantly greater efficacy than placebo. The HBBI study was a multicenter, randomized, double-blind, parallel, placebo- and active-controlled trial. Male and female patients aged 18 to 65 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia were randomized in a 2:2:2:2:2:1 ratio to receive 5-, 20-, 40-, or 80-mg LY2140023 monohydrate twice daily, placebo twice daily, or placebo (am) and 15 mg of olanzapine (pm) daily. Efficacy was defined as the change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score assessed at 4 weeks. The primary analysis did not show that any of the 4 LY2140023 monohydrate doses were more efficacious than placebo as measured by the PANSS total score. Similarly, olanzapine did not significantly separate from placebo. A higher-than-anticipated treatment effect (14.6-point improvement) in the placebo group was observed on PANSS total score. LY2140023 monohydrate was generally well tolerated, although 4 patients reported the serious adverse event of convulsion. LY2140023 monohydrate-treated patients showed little change in dopamine-related adverse events and weight. The results of the HBBI study are considered to be inconclusive because LY2140023 monohydrate and the active control olanzapine did not separate from placebo in the treatment of patients with acutely exacerbated schizophrenia. Additional efficacy, safety, and tolerability testing are needed.