Omigapil(Omigapil) - 药物靶点：GAPDH_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [7]

靶点

GAPDH

作用机制

GAPDH抑制剂(肝甘油醛-3-磷酸脱氢酶抑制剂)

治疗领域

神经系统疾病内分泌与代谢疾病其他疾病+ [2]

在研适应症-

非在研适应症

肌萎缩侧索硬化先天性肌营养不良症肌营养不良+ [2]

原研机构

Santhera Pharmaceuticals (USA), Inc.

在研机构-

非在研机构

Novartis Pharmaceuticals Corp.

Novartis AG

Santhera Pharmaceuticals Holding AG

+ [2]

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (欧盟)

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结构/序列

分子式C19H17NO

InChIKeyQLMMOGWZCFQAPU-UHFFFAOYSA-N

CAS号181296-84-4

关联

6

项与 Omigapil 相关的临床试验

NCT01805024

/ Completed临床1期

Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study Analyzing Pharmacokinetics at Three Dose Levels In Children and Adolescents With Assessment of Safety and Tolerability of Omigapil (CALLISTO)

The purpose of the study is to establish the pharmacokinetic profile of omigapil in paediatric and adolescent patients with CMD and to evaluate the safety and tolerability of omigapil.
Funding source - FDA OOPD

开始日期2014-12-01

申办/合作机构

Santhera Pharmaceuticals (USA), Inc.

EUCTR2004-002855-15-DE

/ Not yet recruitingN/A

A long-term extension to a randomized, double-blind, placebo-controlled, stratified, parallel-group, multicenter, dose-ranging study evaluating four oral doses of TCH346 (1.0, 2.5, 7.5 and 15mg) administered once daily in patients with Amyotrophic Lateral Sclerosis.

开始日期2004-12-29

申办/合作机构

Novartis Pharma Services AG

NCT00230074

/ Completed临床2期

A Long-term Extension Study of TCH346 and Placebo Administered Once Daily in Patients With Amyotrophic Lateral Sclerosis(ALS)

This is a study to evaluate the safety and clinical effects of 4 oral doses of TCH346 compared to placebo in patients with mild or mild to moderate stages of ALS.

开始日期2004-11-01

申办/合作机构

Novartis AG

100 项与 Omigapil 相关的临床结果

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100 项与 Omigapil 相关的转化医学

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100 项与 Omigapil 相关的专利（医药）

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40

项与 Omigapil 相关的文献（医药）

2024-06-01·Neurology Genetics

Phase 1 Open-Label Study of Omigapil in Patients With LAMA2- or COL6-Related Dystrophy

Article

作者: Petraki, Diana ; Hu, Ying ; DeCoster, Jameice ; Zou, Yaqun ; Foley, A Reghan ; Bharucha-Goebel, Diana X ; Jain, Minal S ; Parks, Rebecca ; Mayer, Oscar H ; Bönnemann, Carsten G ; Donkervoort, Sandra ; Leach, Meganne E ; Arévalo, Cynthia ; Waite, Melissa ; Averion, Gilberto V ; Yun, Pomi ; Cheung, Ken ; Mendoza, Christopher ; Hayes, Leslie H ; Neuhaus, Sarah B ; Fink, Margaret ; Hausmann, Rudolf

Background and ObjectivesOmigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dy^w/dy^w) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy^2J/dy^2J) LAMA2-RD mouse model and the (Col6a1^-/-) COL6-RD mouse model demonstrated decreased apoptosis.MethodsA phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data.ResultsTwenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC_0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study.DiscussionThis study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations.Classification of EvidenceThis study provides Class IV evidence of omigapil in a dose-finding phase 1 study.Trial Registration InformationClinical Trials NCT01805024.

2024-03-01·Neural regeneration research

Single-neuron neurodegeneration as a degenerative model for Parkinson's disease.

Review

作者: Segura-Aguilar, Juan ; Huenchuguala, Sandro

The positive effect of levodopa in the treatment of Parkinson's disease, although it is limited in time and has severe side effects, has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons. Successful preclinical studies with coenzyme Q10, mitoquinone, isradipine, nilotinib, TCH346, neurturin, zonisamide, deferiprone, prasinezumab, and cinpanemab prompted clinical trials. However, these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease, despite its severe side effects after 4-6 years of chronic treatment. The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson's disease treatment is a big problem. In our opinion, the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine, that induce a very fast, massive and expansive neurodegenerative process, which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons. The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson's patients is due to (i) a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron, (ii) a neurotoxic event that is not expansive and (iii) the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons. The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome, since it (i) is generated within neuromelanin-containing dopaminergic neurons, (ii) does not cause an expansive neurotoxic effect and (iii) triggers all the mechanisms involved in the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson's disease. In conclusion, based on the hypothesis that the neurodegenerative process of idiopathic Parkinson's disease corresponds to a single-neuron neurodegeneration model, we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2. It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes.

2017-10-01·Translational Stroke Research2区 · 医学

PCMT1 Ameliorates Neuronal Apoptosis by Inhibiting the Activation of MST1 after Subarachnoid Hemorrhage in Rats

2区 · 医学

Article

作者: Zhang, Jianmin ; Chen, Sheng ; Xu, Shenbin ; Al-Baadani, Ammar ; Zhou, Keren ; Shao, Anwen ; Shi, Ligen

Mammalian sterile 20-like kinase 1 (MST1) is found to promote neuronal apoptosis. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1), an anti-apoptosis factor, was recently identified as an MST1-interacting protein. This study aims to explore the potential role of PCMT1 in reducing MST1-induced neuronal apoptosis after subarachnoid hemorrhage (SAH) in rats. One hundred ninety-eight male Sprague-Dawley rats were used. An exogenous PCMT1 agonist, CGP 3466B, was injected subcutaneously 1 h after the SAH induced by endovascular perforation. Chelerythrine or calyculin A was given immediately via intracerebroventricular administration after SAH. The SAH grade, Garcia score, and brain water content were measured at 24 and 72 h after the SAH. Neuronal apoptosis was detected by an immunofluorescent assay. The expression levels of endogenous PCMT1, MST1, phospho-MST1 (p-MST1), cleaved MST1 (cl-MST1), and apoptosis-related proteins were studied by western blotting. The expression of PCMT1 and MST1 decreased, while the level of active caspase 3 increased in rats after SAH. CGP 3466B treatment improved neurobehavioral function, reduced brain water content, inhibited the activity of MST1, and relieved neuronal apoptosis. These neuroprotective effects were significantly weakened either through accelerating MST1 phosphorylation by calyculin A or increasing cl-MST1 by chelerythrine. PCMT1 inhibited neuronal apoptosis by reducing MST1 phosphorylation and the level of cl-MST1. PCMT1/MST1 pathway might be an alternative therapeutic target for alleviating early brain injury after SAH.

100 项与 Omigapil 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	Omigapil	-	DB12879

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
帕金森病（青年型、早发型）	临床2期	英国	Novartis AG	2002-01-01
帕金森病（青年型、早发型）	临床2期	葡萄牙	Novartis AG	2002-01-01
帕金森病（青年型、早发型）	临床2期	荷兰	Novartis AG	2002-01-01
帕金森病（青年型、早发型）	临床2期	巴西	Novartis AG	2002-01-01
帕金森病（青年型、早发型）	临床2期	加拿大	Novartis AG	2002-01-01
帕金森病（青年型、早发型）	临床2期	德国	Novartis AG	2002-01-01
帕金森病（青年型、早发型）	临床2期	法国	Novartis AG	2002-01-01
帕金森病（青年型、早发型）	临床2期	美国	Novartis AG	2002-01-01
帕金森病	临床2期	欧洲	Novartis AG	-
帕金森病	临床2期	欧洲	Novartis AG	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01805024 (CALLISTO, CTgov)	临床1期	先天性肌营养不良症	20	Omigapil (Cohort 1 0.02 mg/kg/Day)	艱獵網壓願鹽糧鹽糧顧(壓夢繭襯餘淵糧鑰衊築) = 蓋製簾簾襯構構憲醖製淵顧網襯衊觸夢夢觸獵 (鏇廠願鹹襯鹹製艱網願, 醖獵廠積壓網鹹顧觸餘 ~ 餘簾艱窪壓鹽壓壓顧獵) 更多	-	2019-09-20
				Omigapil (Cohort 2 0.08 mg/kg/Day)	艱獵網壓願鹽糧鹽糧顧(壓夢繭襯餘淵糧鑰衊築) = 鹽鑰遞積醖蓋鹹廠獵夢淵顧網襯衊觸夢夢觸獵 (鏇廠願鹹襯鹹製艱網願, 艱襯蓋簾壓淵鏇窪憲製 ~ 艱憲衊鏇餘鬱遞衊窪壓) 更多
Pubmed 人工标引	临床2/3期	肌萎缩侧索硬化	591	TCH346 (1.0, 2.5, 7.5, or 15 mg/day)	(繭淵遞築夢構餘製醖窪) = 壓鹽選繭壓積糧鏇鏇構鹽壓選繭襯齋夢鬱構鬱 (齋獵襯襯積製獵鑰鹽簾 ) 未达到	不佳	2007-08-21
				placebo	-