Landipirdine(Landipirdine) - 药物靶点：5-HT2A receptor x 5-HT6 receptor_在研适应症：帕金森病_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Landipirdine (USAN/INN)

+ [5]

靶点

5-HT2A receptor x 5-HT6 receptor

作用方式

拮抗剂

作用机制

5-HT2A receptor拮抗剂(5-羟色胺2A受体拮抗剂)、5-HT6 receptor拮抗剂(5-羟色胺受体6拮抗剂)

治疗领域

神经系统疾病内分泌与代谢疾病

在研适应症

帕金森病

非在研适应症

认知障碍帕金森病所致痴呆

原研机构

F. Hoffmann-La Roche Ltd.

在研机构

F. Hoffmann-La Roche Ltd.

非在研机构

Acorda Therapeutics, Inc.Biotie Therapies Oy

最高研发阶段临床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/序列

分子式C18H19FN2O3S

InChIKeyMTTHRRVVGMPYQG-ZDUSSCGKSA-N

CAS号1000308-25-7

关联

1

项与 Landipirdine 相关的临床试验

NCT02258152

/ Completed临床2期

SYN120 a Dual 5-HT6/5-HT2A Antagonist Proof of Concept Study to Evaluate Its Safety, Tolerability and Efficacy in Parkinson's Disease Dementia (SYNAPSE)

The purpose of this study placebo-controlled, randomized, double-blind study is to assess the safety and efficacy of SYN120 in patients with Parkinson's disease dementia (PDD) already treated with a stable dose of a cholinesterase inhibitor.

开始日期2014-12-22

申办/合作机构

Biotie Therapies Oy

[+3]

100 项与 Landipirdine 相关的临床结果

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100 项与 Landipirdine 相关的转化医学

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100 项与 Landipirdine 相关的专利（医药）

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10

项与 Landipirdine 相关的文献（医药）

2023-09-01·Parkinsonism & related disorders

Safety, tolerability, and preliminary efficacy of SYN120, a dual 5-HT6/5-HT2A antagonist, for the treatment of Parkinson disease dementia: A randomized, controlled, proof-of-concept trial.

Article

作者: Litvan, Irene ; Eberling, Jamie ; Macklin, Eric ; Videnovic, Aleksandar ; Weintraub, Daniel ; Fernandez, Hubert H ; Schwarzschild, Michael A ; Kenney, Christopher J

BACKGROUNDSYN120 is a dual serotonin receptor (5-HT6/5-HT2A) antagonist hypothesized to improve cognition and psychiatric symptoms.OBJECTIVESWe evaluated the safety, tolerability, and efficacy of SYN120 in patients with Parkinson disease dementia (PDD).METHODSIn a multicenter, double-blind, parallel-group, 16-week phase 2a proof-of-concept trial in PDD with concomitant cholinesterase inhibitor use, eligible patients were randomized to oral SYN120 (100 mg/day) or placebo. Adverse events (AEs), Unified Parkinson's Disease Rating Scale (UPDRS) scores, and discontinuations assessed safety and tolerability. The primary and key secondary efficacy measures were the Cognitive Drug Research (CDR) computerized assessment system Continuity of Attention and Quality of Episodic Memory scores. Other efficacy measures were: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), Brief Penn Parkinson's Daily Activity Questionnaire-15 (PDAQ-15), Scales for Outcomes in Parkinson's Disease-Sleep Scale (SCOPA-Sleep), and Neuropsychiatric Inventory (NPI).RESULTSEighty-two patients were randomized to SYN120 (N = 38) or placebo (N = 44), AEs occurred in 74% and 77% of patients, and treatment discontinuation in both groups was 16%. Nausea and vomiting were more frequent, and motor symptoms (UPDRS) worsened in the SYN120 group. At week 16, the SYN120 and placebo groups did not differ significantly for any cognitive assessment. Cognitive activities of daily living (PDAQ-15) and the NPI-Apathy/Indifference scores improved nominally in the SYN120 group compared with placebo (unadjusted p = 0.029 and 0.028).CONCLUSIONSSYN120 was adequately tolerated, mild worsening of motor symptoms was noted and it did not improve cognition in PDD patients. Its potential benefits for cognitive activities of daily living and apathy warrant further study.REGISTRATIONClinicaltrials.gov as NCT02258152.

2022-12-01·Journal of Neuroinflammation1区 · 医学

Dopamine signaling modulates microglial NLRP3 inflammasome activation: implications for Parkinson’s disease

1区 · 医学

ArticleOA

作者: Teunissen, Charlotte E ; Hoozemans, Jeroen J M ; Gombert, Iris ; Bubacco, Luigi ; van Eik, Jean-Marc ; Herrebout, Maaike A C ; Fayed, Mona M H E ; Pike, Adrianne F ; Varanita, Tatiana ; Faustini, Gaia ; Sandre, Michele ; Bellucci, Arianna ; Longhena, Francesca ; Veerhuis, Robert

AbstractBackgroundParkinson’s disease (PD) is characterized by the loss of nigral dopaminergic neurons leading to impaired striatal dopamine signaling, α-synuclein- (α-syn-) rich inclusions, and neuroinflammation. Degenerating neurons are surrounded by activated microglia with increased secretion of interleukin-1β (IL-1β), driven largely by the NLRP3 inflammasome. A critical role for microglial NLRP3 inflammasome activation in the progression of both dopaminergic neurodegeneration and α-syn pathology has been demonstrated in parkinsonism mouse models. Fibrillar α-syn activates this inflammasome in mouse and human macrophages, and we have shown previously that the same holds true for primary human microglia. Dopamine blocks microglial NLRP3 inflammasome activation in the MPTP model, but its effects in this framework, highly relevant to PD, remain unexplored in primary human microglia and in other in vivo parkinsonism models.MethodsBiochemical techniques including quantification of IL-1β secretion and confocal microscopy were employed to gain insight into dopamine signaling-mediated inhibition of the NLRP3 inflammasome mechanism in primary human microglia and the SYN120 transgenic mouse model. Dopamine and related metabolites were applied to human microglia together with various inflammasome activating stimuli. The involvement of the receptors through which these catecholamines were predicted to act were assessed with agonists in both species.ResultsWe show in primary human microglia that dopamine, l-DOPA, and high extracellular K+, but not norepinephrine and epinephrine, block canonical, non-canonical, and α-syn-mediated NLRP3 inflammasome-driven IL-1β secretion. This suggests that dopamine acts as an inflammasome inhibitor in human microglia. Accordingly, we provide evidence that dopamine exerts its inhibitory effect through dopamine receptor D1 and D2 (DRD1 and DRD2) signaling. We also show that aged mice transgenic for human C-terminally truncated (1–120) α-syn (SYN120 tg mice) display increased NLRP3 inflammasome activation in comparison to WT mice that is diminished upon DRD1 agonism.ConclusionsDopamine inhibits canonical, non-canonical, and α-syn-mediated activation of the NLRP3 inflammasome in primary human microglia, as does high extracellular K+. We suggest that dopamine serves as an endogenous repressor of the K+ efflux-dependent microglial NLRP3 inflammasome activation that contributes to dopaminergic neurodegeneration in PD, and that this reciprocation may account for the specific vulnerability of these neurons to disease pathology.

2017-05-17·ACS Chemical Neuroscience3区 · 医学

Serotonergic Approaches in Parkinson’s Disease: Translational Perspectives, an Update

3区 · 医学

Review

作者: Fox, Susan H. ; Huot, Philippe ; Sgambato-Faure, Véronique ; McCreary, Andrew C.

Parkinson's disease (PD) has long been seen as a disorder caused by degeneration of the dopaminergic system, leading to the classic motor manifestations of the disease. However, there is now overwhelming evidence that PD is more than a disease merely caused by dopamine depletion. It is well-known that a myriad of other neurotransmitters are affected by the disease process. One such neurotransmitter is serotonin (5-HT). 5-HT has been shown to play a role in several motor and nonmotor manifestations of PD, including tremor, cognition, depression and psychosis. 5-HT also seems to play a critical role in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. A breadth of preclinical studies and clinical trials have been conducted that aimed at modulating the 5-HT system in order to alleviate depression, cognitive deficits, psychosis, and dyskinesia. In this Review, we summarize recent advances in the 5-HT field in PD, but with a translational emphasis. We start by presenting a novel nonhuman primate model of PD that presents with dual dopamine and 5-HT lesions. We then present preclinical and clinical data that introduce new concepts, such as the use of biased and partial agonists, as well as molecules recently introduced to the field of PD, such as eltoprazine, pimavanserin, nelotanserin, and SYN-120, to enhance therapeutic benefit while minimizing adverse events, notably on parkinsonian disability.

100 项与 Landipirdine 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11157	-	-	DB16214

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	临床2期	-	F. Hoffmann-La Roche Ltd.	-
帕金森病所致痴呆	临床1期	美国	Acorda Therapeutics, Inc.	2014-12-22
认知障碍	临床前	美国	Biotie Therapies Oy	-

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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


NCT02258152 (SYNAPSE, CTgov)	临床2期	帕金森病所致痴呆	82	Placebo (Placebo)	築鹽憲製壓鑰蓋憲壓鹽(範衊艱餘膚壓夢蓋衊積) = 襯積齋繭選淵衊網壓壓憲蓋膚願鹽願繭鬱觸鏇 (願願繭憲簾遞蓋繭鏇夢, 製窪鹹憲鑰醖膚獵憲繭 ~ 鑰鏇繭餘糧廠鹽艱積齋) 更多	-	2019-04-19
				SYN120 (SYN120)	築鹽憲製壓鑰蓋憲壓鹽(範衊艱餘膚壓夢蓋衊積) = 網壓選淵遞餘構顧蓋淵憲蓋膚願鹽願繭鬱觸鏇 (願願繭憲簾遞蓋繭鏇夢, 鬱襯糧廠壓鏇鏇遞獵獵 ~ 憲鬱憲鹹鑰簾鏇壓衊膚) 更多
NCT02258152 (SYNAPSE, MDS2018)	临床2期	非典型进行性核上性麻痹	82	SYN120 100 mg daily	顧鬱顧壓鑰鏇簾廠觸製(襯膚鑰製壓觸蓋製壓壓) = incidence of nausea and vomiting were two-fold higher with SYN120 餘築鬱選淵衊繭襯製獵 (鬱蓋顧鏇積鹽醖觸選壓 ) 更多	不佳	2018-10-05
				Placebo
MDS2018	临床2期	非典型进行性核上性麻痹	-	SYN120 100 mg daily	網醖構築鑰蓋簾構獵艱(鏇襯膚壓餘壓範齋觸鬱) = Numerical improvements with SYN120 compared to placebo were also noted for SCOPA-SLEEP nighttime sleep (ES=0.47; p=0.05) 構餘窪鬱艱願鬱廠餘鹹 (鏇憲構鹽構簾窪選衊範 ) 更多	-	2018-10-05
				Placebo