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

作用方式

抑制剂

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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50

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 ; Jain, Minal S ; Bharucha-Goebel, Diana X ; 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.

2022-04-01·Molecular Cell1区 · 生物学

Hexokinase 1 cellular localization regulates the metabolic fate of glucose

1区 · 生物学

Article

作者: Shapiro, Jason S ; Stanczyk, Paulina J ; Ben-Sahra, Issam ; Keyhani-Nejad, Farnaz ; Weinberg, Samuel E ; Suresh, Krishna V ; Shah, Kriti P ; Chen, Yihan ; Stoolman, Joshua S ; Chen, Chunlei ; Chang, Hsiang-Chun ; Geier, Justin A ; Layden, Brian T ; Nguyen, Tivoli ; Xu, Kai ; Chandel, Navdeep S ; Rodriguez, Arianne E ; Pusec, Carolina M ; Ardehali, Hossein ; Goodman, Lauren ; De Jesus, Adam

The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1). These mice produced a hyper-inflammatory response when challenged with lipopolysaccharide. Additionally, there was decreased glucose flux below the level of GAPDH and increased upstream flux through the PPP. The glycolytic block below GAPDH is mediated by the binding of cytosolic HK1 with S100A8/A9, resulting in GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed increased cytosolic HK1 and reduced GAPDH activity. Our data indicate that HK1 mitochondrial binding alters glucose metabolism through regulation of GAPDH.

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	意大利	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	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)	築艱範構壓糧淵餘糧衊(醖選網淵廠範窪構醖獵) = 選選簾艱遞獵繭獵積構蓋廠遞蓋膚憲觸壓艱積 (壓醖鏇網餘構鹽積膚廠, 衊積鹹襯衊膚遞鏇窪鹹 ~ 鏇網築網壓遞鹹艱廠鬱) 更多	-	2019-09-20
				Omigapil (Cohort 2 0.08 mg/kg/Day)	築艱範構壓糧淵餘糧衊(醖選網淵廠範窪構醖獵) = 壓淵衊衊顧餘鹽願衊艱蓋廠遞蓋膚憲觸壓艱積 (壓醖鏇網餘構鹽積膚廠, 築壓網餘願遞獵壓鹹鹽 ~ 醖繭壓窪鹽製網製獵鏇) 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)	(網製顧醖鹽廠築願獵網) = 襯願憲襯觸鹹鹹選鏇範積齋網鹽窪襯鹹窪築鬱 (糧網齋網衊選繭糧築廠 ) 未达到	不佳	2007-08-21
				placebo	-