Sembragiline(Sembragiline) - 药物靶点：MAO-B_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Sembragiline (USAN/INN)

+ [1]

靶点

MAO-B

作用机制

MAO-B抑制剂(单胺氧化酶B抑制剂)

治疗领域

神经系统疾病其他疾病

在研适应症-

非在研适应症

阿尔茨海默症尼古丁成瘾

原研机构

F. Hoffmann-La Roche Ltd.

在研机构-

非在研机构

Evotec International GmbHHoffmann-La Roche, Inc.

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C19H19FN2O3

InChIKeyVMAVCCUQTALHOB-INIZCTEOSA-N

CAS号676479-06-4

关联

9

项与 Sembragiline 相关的临床试验

JPRN-jRCT2080222554 / Unknown status临床1期

A multi center, open label study to assess the inhibiton of Brain MAO-B by RG1577 after repeated dosing in Japanese patients with Alzheimers Disease using positron emission tomography (PET)

开始日期2014-07-07

申办/合作机构

Chugai Pharmaceutical Co., Ltd.

NCT02104648 / Completed临床1期

A 2 PART STUDY IN HEALTHY SUBJECTS: PART A: A MULTIPLE DOSE, RANDOMIZED, PLACEBO CONTROLLED STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF SUPRA-THERAPEUTIC DOSES OF RO4602522; PART B: A MULTIPLE-DOSE, RANDOMIZED, DOUBLE-BLIND, DOUBLE DUMMY, PLACEBO CONTROLLED, POSITIVE-CONTROL, PARALLEL GROUP STUDY TO INVESTIGATE THE EFFECT OF RO4602522 ON THE QTC INTERVAL

This is a 2 part study to evaluate the safety and tolerability of supra-therapeutic doses of RO4602522 (Part A); and to investigate the effect of RO4602522 on the QTcF interval in healthy volunteers (Part B). Part A of the study will be a multiple-dose, randomized, double-blind, placebo-controlled study. Participants will be randomized to receive daily, oral doses of either RO4602522 or placebo for ten days. Part B of the study will be a multiple-dose, randomized, double-blind, double-dummy, placebo controlled, positive-control, parallel group study. Participants will be randomized to receive either multiple or single doses of RO4602522 or to receive single doses of moxifloxacin for 11 days. Pharmacokinetic parameters will be assessed for Parts A and B; and continuous ECG recordings will be made during Part B.

开始日期2014-04-01

申办/合作机构

Hoffmann-La Roche, Inc.

JPRN-JapicCTI-142605 / Unknown status临床1期

A multi center, open label study to assess the inhibiton of Brain MAO-B by RG1577 after repeated dosing in Japanese patients with Alzheimers Disease using positron emission tomography (PET)

开始日期2014-04-01

申办/合作机构

Chugai Pharmaceutical Co., Ltd.

100 项与 Sembragiline 相关的临床结果

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100 项与 Sembragiline 相关的转化医学

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100 项与 Sembragiline 相关的专利（医药）

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6

项与 Sembragiline 相关的文献（医药）

2018-01-01·Bioorganic & Medicinal Chemistry3区 · 医学

Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson’s disease therapy

3区 · 医学

Article

作者: Siwon Kim ; Hyeon Jeong Kim ; Yong Sup Lee ; Seul Ki Yeon ; Gyoonhee Han ; Ki Duk Park ; Ji Won Choi ; Jong Hyun Park ; Ae Nim Pae ; Yong Sun Bahn ; Bo Ko Jang ; Su Jeong Shin ; Ye Rim Lee

Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC₅₀: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor. In addition, 12c showed greater MAO-B inhibitory activity and selectivity compared to well-known MAO-B inhibitors such as selegiline, safinamide and sembragiline. In the MPTP-induced mouse model of Parkinson's disease (PD), 12c significantly protected the tyrosine hydroxylase (TH)-immunopositive DAergic neurons and attenuated the PD-associated behavioral deficits. This study suggests characteristic structures as a MAO-B inhibitor that may provide a good insight for the development of therapeutic agents for PD.

2017-09-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

Sembragiline: A Novel, Selective Monoamine Oxidase Type B Inhibitor for the Treatment of Alzheimer’s Disease

3区 · 医学

Article

作者: Andersen, Julie K ; Messer, Juerg ; Siddiqui, Almas ; Rajagopalan, Subramanian ; Cesura, Andrea M ; Chinta, Shankar J ; Nave, Stephane ; Grueninger, Fiona ; Wyler, Rene ; Bohrmann, Bernd ; Rane, Anand ; Pähler, Axel ; Loetscher, Hansruedi ; Ellenbroek, Bart ; Prinssen, Eric ; Borroni, Edilio

Monoamine oxidase B (MAO-B) has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased MAO-B expression in astroglia has been observed adjacent to amyloid plaques in AD patient brains. This phenomenon is hypothesized to lead to increased production of hydrogen peroxide and reactive oxygen species (ROS), thereby contributing to AD pathology. Therefore, reduction of ROS-induced oxidative stress via inhibition of MAO-B activity may delay the progression of the disease. In the present study we report the pharmacological properties of sembragiline, a novel selective MAO-B inhibitor specifically developed for the treatment of AD, and on its effect on ROS-mediated neuronal injury and astrogliosis in MAO-B transgenic animals. Sembragiline showed potent and long-lasting MAO-B-selective inhibition and did not inhibit MAO-A at doses where full inhibition of MAO-B was observed. Such selectivity should translate into a favorable clinical safety profile. Indeed, sembragiline neither induced the serotonin syndrome when administered together with the serotonin precursor l-5-hydroxytryptophan in combination with antidepressants such as fluoxetine, nor potentiated the pressor effect of tyramine. Additionally, in experiments using a transgenic animal model conditionally overexpressing MAO-B in astroglia, sembragiline protected against neuronal loss and reduced both ROS formation and reactive astrogliosis. Taken together, these findings warrant further investigation of the potential therapeutic benefit of MAO-B inhibitors in patients with AD and other neurologic disorders.

2017-06-23·Journal of Alzheimer's Disease3区 · 医学

Sembragiline in Moderate Alzheimer’s Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD)

3区 · 医学

Article

作者: Fontoura, Paulo ; Ricci, Benedicte ; Czech, Christian ; Nikolcheva, Tania ; Delmar, Paul ; Nave, Stephane ; Muelhardt, Nicoletta Milani ; Savola, Juha-Matti ; Dukart, Juergen ; Gilaberte, Inma ; Mannino, Marie ; Grimmer, Timo ; Doody, Rachelle S. ; Boada, Merce ; Pauly-Evers, Meike ; Lanctot, Krista ; Gerlach, Irene ; Carey, Tracie ; Borroni, Edilio ; Moran, Emma ; Santarelli, Luca ; Ostrowitzki, Susanne

BACKGROUNDSembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD).OBJECTIVETo evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD.METHODSIn this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13-20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks.RESULTSNo differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was - 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: - 2.80 (p = 0.014; 1 mg) and - 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median).CONCLUSIONSThis study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.

100 项与 Sembragiline 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11224	-	-	-

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
阿尔茨海默症	临床2期	捷克	Hoffmann-La Roche, Inc.	2012-10-24
阿尔茨海默症	临床2期	德国	Hoffmann-La Roche, Inc.	2012-10-24
阿尔茨海默症	临床2期	英国	Hoffmann-La Roche, Inc.	2012-10-24
阿尔茨海默症	临床2期	波兰	Hoffmann-La Roche, Inc.	2012-10-24
阿尔茨海默症	临床2期	澳大利亚	Hoffmann-La Roche, Inc.	2012-10-24
阿尔茨海默症	临床2期	美国	Hoffmann-La Roche, Inc.	2012-10-24
阿尔茨海默症	临床2期	瑞典	Hoffmann-La Roche, Inc.	2012-10-24
阿尔茨海默症	临床2期	加拿大	Hoffmann-La Roche, Inc.	2012-10-24
阿尔茨海默症	临床2期	韩国	Hoffmann-La Roche, Inc.	2012-10-24
尼古丁成瘾	临床2期	德国	Evotec International GmbH	2008-02-01

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临床结果

适应症

分期

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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


AAIC2013	N/A	阿尔茨海默症	-	RO4602522 (AD patients)	製糧鹹鑰憲窪構廠膚壓(蓋遞簾築獵蓋艱鑰網簾) = 窪觸壓願衊鹽壓糧淵鹹鬱蓋鹽鹹選糧鹹齋築構 (衊築廠選廠夢網顧鹹蓋 )	-	2013-07-01