PF-02545920(PF-02545920) - 药物靶点：PDE10A_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Mardepodect

+ [1]

靶点

PDE10A

作用机制

PDE10A抑制剂(磷酸二酯酶10A抑制剂)

治疗领域

神经系统疾病遗传病与畸形其他疾病

在研适应症-

非在研适应症

急性精神分裂症亨廷顿舞蹈病分裂情感性障碍+ [1]

原研机构

Pfizer Inc.

在研机构-

非在研机构

Pfizer Inc.

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-

结构

分子式C25H20N4O

InChIKeyAZEXWHKOMMASPA-UHFFFAOYSA-N

CAS号898562-94-2

关联

12

项与 PF-02545920 相关的临床试验

NCT02342548 / Terminated临床2期

An Open Label Extension Study To Investigate The Long Term Safety, Tolerability And Efficacy Of Pf-02545920 In Subjects With Huntington's Disease Who Previously Completed Study A8241021

This study is a 12 month open label extension study of PF-02545920 20 mg dosed BID following study A8241021 in subjects with HD. Primary endpoints will be to assess long-term safety and tolerability of 20 mg BID of PF-02545920. Secondary endpoints will be the change from baseline in the Total Motor Score (TMS)assessment, and/ior the Total maximum Chorea (TMC) assessment of the Unified Huntington Disease Rating Scale (UHDRS) after 6 and 12 months of treatment, and Clinical Global Impression-Improvement score after 6 and 12 months of treatment. Subjects, who were assigned to the 20 mg PF-02545920 dose group in the preceding A8241021 study, will receive 20 mg PF-02545920 without any titration. All other subjects will be titrated to the 20 mg BID dose as follows: 5 mg BID for 7 days, 10 mg BID for 7 days, 15 mg BID for 7 days, then 20 mg BID for the remainder of the treatment phase. Up to 260 subjects may take part in this open label extension

开始日期2015-02-25

申办/合作机构

Pfizer Inc.

NCT02197130 / Completed临床2期

A Phase 2, Randomized, Placebo Controlled, Double Blind Proof-of-concept Study Of The Efficacy And Safety Of Pf-02545920 In Subjects With Huntington's Disease

This study is a 26 week, randomized, parallel group, double blind comparison of PF-02545920 5 mg, PF-02545920 20 mg, and placebo dosed BID in the treatment of motor impairment of subjects with Huntington's Disease. A total of approximately 260 subjects are planned to be randomized in the study. Primary endpoint is the change from baseline in the Total Motor Score (TMS) assessment of the Unified Huntington Disease Rating Scale (UHDRS) after 26 weeks of treatment. secondary endpoints will include change from baseline in the Total Maximum Chorea (TMC) score of the UHDRS after 13 and 26 weeks of treatment and Clinical Global Impression-Improvement score after 13 and 26 weeks of treatment.

开始日期2014-09-01

申办/合作机构

Pfizer Inc.

NCT01918202 / Completed临床1期

A Phase 1, Open-label Adaptive Design Study To Evaluate Pde10 Enzyme Occupancy As Measured By Positron Emission Tomography (Pet) Following Single Oral Dose Administration Of Pf-02545920 In Healthy Male Subjects

This Phase 1 study will evaluate PDE10 enzyme occupancy using Positron Emission Tomography after a single dose of PF-02545920 in Healthy male volunteers.

开始日期2014-03-01

申办/合作机构

Pfizer Inc.

100 项与 PF-02545920 相关的临床结果

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100 项与 PF-02545920 相关的转化医学

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100 项与 PF-02545920 相关的专利（医药）

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42

项与 PF-02545920 相关的文献（医药）

2023-09-01·Asian Journal of Andrology

Phosphodiesterase 10A inhibitor PF-2545920 as a prospective agent for the clinical promotion of sperm motility

Article

作者: Wang, Wei-Wei ; Li, Yu-Hua ; Yan, Bin ; Diao, Hua ; Guo, Li-Na ; Yu, He-Guo ; Yang, Yi-Ting ; Liu, Li-Jie

Phosphodiesterase (PDE) inhibitors can improve sperm motility in patients with asthenozoospermia. However, the most commonly reported nonselective PDE inhibitor pentoxifylline and PDE5 inhibitor sildenafil have the disadvantages of requiring a high concentration and destroying sperm integrity. We examined the PDE10A inhibitor PF-2545920 to compare its ability to promote sperm motility with that of pentoxifylline and sildenafil. After seminal plasma was discarded, several semen samples were subjected to four treatments (control, PF-2545920, pentoxifylline, and sildenafil) to evaluate their ability to affect motility, viability, and spontaneous acrosome reactions. Intracellular calcium and adenosine triphosphate (ATP), mitochondrial membrane potential, and penetration through viscous medium were assessed by flow cytometry, luciferase, and hyaluronic acid after treatment with PF-2545920. Statistical analyses were performed using the analysis of variance statistical test. PF-2545920 elevated the percentage of motile spermatozoa compared to the control, pentoxifylline, and sildenafil groups at 10 µmol l−1 (P < 0.01). It is less toxic to GC-2spd mouse spermatocytes cells and spermatozoa and causes fewer spontaneous acrosomal reactions (P < 0.05). PF-2545920 also increased mitochondrial membrane potential (P < 0.001) and altered intracellular calcium (P < 0.05) in a dose-dependent manner, including increasing sperm hyaluronic acid penetrating ability (P < 0.05). Therefore, PF-2545920 might be an excellent choice for stimulating the sperm motility.

2021-06-01·Journal of Neuroimmune Pharmacology3区 · 医学

The Potent PDE10A Inhibitor MP-10 (PF-2545920) Suppresses Microglial Activation in LPS-Induced Neuroinflammation and MPTP-Induced Parkinson’s Disease Mouse Models

3区 · 医学

Article

作者: Kim, Hee-Sun ; Leem, Yea-Hyun ; Kim, Do-Yeon ; Park, Jin-Sun ; Park, Jung-Eun

MP-10 (PF-2545920) is a selective inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly enriched in the striatum, nucleus accumbens, olfactory tubercle, and substantia nigra. The therapeutic effect of MP-10 has been reported in psychiatric and neurodegenerative disorders such as schizophrenia, depression, and Huntington's disease. However, the effect of MP-10 in Parkinson's disease (PD) has not been reported to date. In this study, we examined the effect of MP-10 in neuroinflammation and PD mouse models. MP-10 inhibited nitric oxide, tumor necrosis factor alpha, and interleukin (IL)-6 production, while it promoted IL-10 production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Subsequent western blot and reverse transcription polymerase chain reaction analyses showed that MP-10 reduced the mRNA and protein levels of inducible nitric oxide synthase, cyclooxygenase-2, proinflammatory cytokines, and matrix metalloproteinase-3, -8, and - 9 in LPS-stimulated BV2 cells. Further mechanistic studies revealed that MP-10 exerts anti-inflammatory effects by inhibiting the phosphorylation of c-Jun N-terminal kinase and Akt, reducing the activity of nuclear factor-kappa B/activator protein-1, and upregulating the nuclear factor erythroid 2-related factor 2/antioxidant response element and protein kinase A/cAMP response element-binding protein signaling pathways. The anti-inflammatory effect of MP-10 was confirmed in vivo. Specifically, MP-10 inhibited microglial activation and proinflammatory gene expression in the brains of LPS-injected mice. Moreover, MP-10 rescued behavioral deficits and recovered dopaminergic neuronal cell death in the brains of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice. MP-10 also reduced microglial activation in this PD mouse model. These data collectively suggest that MP-10 may have therapeutic potential in PD and other neuroinflammatory disorders. Graphical Abstract.

2019-11-01·Journal of Clinical Psychopharmacology4区 · 医学

Phosphodiesterase 10A Inhibitor Monotherapy Is Not an Effective Treatment of Acute Schizophrenia

4区 · 医学

Article

作者: DeMartinis, Nicholas ; Schmidt, Christopher J ; Banerjee, Anindita ; Walling, David P ; Boyer, Stacey ; Dawra, Vikas

AbstractBackgroundCurrent treatments for psychotic symptoms associated with schizophrenia often provide inadequate efficacy with unacceptable adverse effects. Improved therapeutics have long been a goal of research. Preclinical testing suggests that phosphodiesterase 10A (PDE10A) inhibitors may provide a novel approach to treating psychosis associated with schizophrenia.MethodsThe efficacy and safety of a highly selective PDE10A inhibitor, PF-02545920, was evaluated in a phase 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eligible patients (18–65 years) with an acute exacerbation of schizophrenia were randomized 2:2:1:2 to PF-02545920 (5 or 15 mg every 12 hours [Q12H] titrated), risperidone (3 mg Q12H), or placebo for 28 days (n = 74:74:37:74). The primary objectives were to evaluate the efficacy of PF-02545920 using the Positive and Negative Syndrome Scale (PANNS) and safety/tolerability.ResultsAt day 28, PF-02545920 (either dose) was not significantly different from placebo for mean change from baseline in the PANNS total score (primary end point) or most other end points. Pharmacokinetics exposures seemed adequate for binding/inhibiting PDE10A enzyme. Risperidone was statistically different from placebo for the PANNS total score, demonstrating study sensitivity. Incidence rates for adverse events were similar among the groups. Both doses of PF-02545920 were generally well tolerated. Dystonia occurred in 1, 6, 0, and 3 patients in the PF-02545920 5 mg Q12H, PF-02545920 15 mg Q12H, risperidone, and placebo groups, respectively.ConclusionsNeither dose of PF-02545920 was superior to placebo for the primary and most secondary end points. This indicates that PDE10A inhibition does not produce an antipsychotic effect in patients with acute exacerbation of schizophrenia.

1

项与 PF-02545920 相关的新闻（医药）

2023-07-25

·生物谷

《自然·神经科学》：颠覆认知！美国西北大学团队发现，抗精神分裂药物的作用机制与预想的不一样

近日，美国西北大学的研究团队获得了精神病神经基础理解的里程碑式发现——与抗精神病药物相结合调控纹状体输出并不是D2R，而是D1R。精神分裂症是一种严重的精神障碍，患者可能出现感知、思维和情感方面的严重紊乱，对日常生活产生十分恶劣的影响。多巴胺假说是精神分裂症发病机制的重要假说之一。多巴胺假说认为，精神分裂症可能与大脑中多巴胺的过度活跃有关。过度活跃的神经递质导致特定神经回路的失衡，从而引发幻觉、妄想、思维紊乱、情感疏离等症状。抑制多巴胺活性被认为是抗精神病药物的主要作用机制之一。大脑纹状体区域的棘状投射神经元（SPNs）分别表达多巴胺受体D1（D1R）和多巴胺受体D2（D2R），受体与Gαs偶联可以增加或降低SPN活动。通过调节SPN，可以达到平衡纹状体输出的目的。以往科学家认为，抗精神病药物是通过与D2R结合来抑制多巴胺活性的。事实上，D2R在纹状体之外的脑细胞中也有表达，根据受体表达水平预测的药物治疗效果往往与实际存在误差甚至完全相反。近日，美国西北大学的研究团队获得了精神病神经基础理解的里程碑式发现——与抗精神病药物相结合调控纹状体输出并不是D2R，而是D1R。研究发现，有些药物虽然能够使D2-SPN动态正常化，但是却没有产生临床效果。药物的抗精神病功效与D1-SPN的动力学逆转有关。选择性抑制D1-SPN可以减弱安非他命驱动的过度运动、幻觉等症状。研究发表在《自然·神经科学》上。研究人员通过神经群体成像方法记录小鼠大脑D1-SPN和D2-SPN的活动。使用安非他命诱导多巴胺释放，神经元活动与之前观察的一致，D1-SPN活动水平增加，D2-SPN活动水平降低。接下来，研究人员选择了4种抗精神病药物，评估其对神经元活动的影响。其中，氟哌啶醇有显著的运动障碍副作用，氯氮平和奥氮平运动障碍副作用较轻，MP-10为临床失败的精神分裂症候选药物。根据小鼠用药后的运动能力，设置高、低两种药物剂量。结果显示，3种临床有效药物均可以减轻安非他命引起的D1-SPN神经元动态紊乱、过度运动和感觉运动门控异常（即感觉和运动之间的调节失常）。相比之下，MP-10虽然减轻了安非他命引起的D2-SPN活动水平降低，但是加剧了D1-SPN的过度活动，且并未纠正小鼠的感觉运动门控异常。抗精神病药物改善小鼠的过度运动这样的结果提示我们，是不是对D1-SPN活动的纠正，才是药物起效的关键呢？研究人员用其他新型抗精神病药物候选化合物进行了测试。虽然这些化合物的作用机制并不是与多巴胺受体结合，但所有产生临床疗效的化合物，都可以减轻安非他命引起的D1-SPN过度活动。而通过化学方法抑制D1-SPN活性，也可以减轻安非他命导致的小鼠幻听。药物对D1-SPN的影响能更好地解释抗精神病药物的疗效分别使用D1R部分激动剂SKF38393、D1R拮抗剂SCH23390/SCH39166处理小鼠，结果显示，3种化合物可以减轻安非他命引起的过度运动和感觉运动门控异常。其中，SKF38393在基线条件下促进D1-SPN活动，在多巴胺过度释放的条件下抑制D1-SPN活动，表现出多巴胺状态依赖性的D1-SPN选择性抑制。总的来说，研究证明，抗精神病药物的疗效与其恢复D1-SPN的正常活动有关，为开发副作用更小的药物开辟了新的选择。研究人员表示，“这是一个里程碑式发现，彻底改变了我们对精神病神经基础的理解”。

核酸药物

100 项与 PF-02545920 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	PF-02545920	-	DB08387

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
精神分裂症	临床2期	美国	Pfizer Inc.	2013-10-01
亨廷顿舞蹈病	临床2期	法国	Pfizer Inc.	2013-09-01
亨廷顿舞蹈病	临床2期	法国	Pfizer Inc.	2013-09-01
急性精神分裂症	临床2期	美国	Pfizer Inc.	2007-11-01
急性精神分裂症	临床2期	美国	Pfizer Inc.	2007-11-01
分裂情感性障碍	临床2期	南非	Pfizer Inc.	2006-10-01

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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


NCT01939548 \| NCT01829048 (Pubmed) 人工标引	临床2期	精神分裂症辅助	240	PF-02545920	(顧鬱觸網範餘選繭鹽簾) = Treatment was well tolerated, and observed PF-02545920 exposures were within the range predicted to be adequate for demonstrating efficacy 獵糧膚蓋遞範齋憲鏇觸 (窪窪醖鬱繭鬱糧餘遞壓 )	不佳	2019-01-01
				Placebo
NCT01829048 (CTgov)	临床1期	精神分裂症	37	PF-02545920 (PF-02545920 (Cohort 1))	夢鏇鹹構廠構夢夢簾範(窪願膚築繭觸窪艱蓋襯) = 構觸願齋鏇範遞餘壓積壓壓網襯範範願鏇醖願 (壓繭糧繭願壓鹹網憲襯, 夢製積選積獵夢淵淵窪 ~ 醖齋襯鑰廠築選鹽範餘) 更多	-	2018-08-20
				PF-02545920 (PF-02545920 (Cohort 2))	夢鏇鹹構廠構夢夢簾範(窪願膚築繭觸窪艱蓋襯) = 願願鏇齋艱醖廠蓋製網壓壓網襯範範願鏇醖願 (壓繭糧繭願壓鹹網憲襯, 蓋淵夢鑰網窪膚遞範簾 ~ 淵繭顧壓鬱構憲顧醖衊) 更多
NCT02342548 (CTgov)	临床2期	亨廷顿舞蹈病	188	PF-02545920 (20 mg PF-02545920)	(壓醖鹹蓋膚壓構壓壓壓) = 獵簾繭夢範繭艱淵獵淵築壓壓顧餘願繭獵願構 (淵艱繭繭獵鹹鹽淵襯願, 積憲鑰獵淵膚廠遞鏇糧 ~ 襯遞選鏇餘糧糧壓糧廠) 更多	-	2018-04-23
				PF-02545920 (5 mg PF-02545920 Titration up to 20 mg)	(壓醖鹹蓋膚壓構壓壓壓) = 蓋淵廠襯窪築鹽範鹽夢築壓壓顧餘願繭獵願構 (淵艱繭繭獵鹹鹽淵襯願, 網製鑰淵醖鏇製積願顧 ~ 醖淵窪蓋顧願壓壓構餘) 更多
NCT01175135 (CTgov)	临床2期	急性精神分裂症	259	PF-02545920 (PF-02545920 5 mg)	鑰衊淵鹹範艱壓鬱壓鬱(觸築鬱糧築觸窪齋製範) = 齋憲窪膚鹽醖襯獵艱鹽鹽鑰積鑰窪顧衊築鹽衊 (淵簾觸製構壓餘廠網壓, 齋窪齋醖醖願膚鹽艱壓 ~ 鑰廠觸襯鑰衊積廠衊壓) 更多	-	2018-03-20
				PF-02545920 (PF-02545920 15 mg)	鑰衊淵鹹範艱壓鬱壓鬱(觸築鬱糧築觸窪齋製範) = 廠壓鑰夢願壓壓襯齋憲鹽鑰積鑰窪顧衊築鹽衊 (淵簾觸製構壓餘廠網壓, 鑰夢鬱鹹觸淵鹽淵鹽壓 ~ 鬱選繭顧蓋鑰壓鑰選鹹) 更多
NCT00570063 (CTgov)	临床2期	急性精神分裂症	35	PF-02545920 (PF-02545920 15 Milligram (mg))	積醖淵窪窪衊積廠膚艱(艱簾齋範選艱夢蓋憲蓋) = 觸餘餘壓憲網鏇窪選鏇構壓廠願鹽醖鬱廠膚鏇 (遞窪範衊構窪鏇構衊窪, 壓鏇廠壓遞衊艱醖築淵 ~ 糧網範網簾簾繭壓鑰繭) 更多	-	2017-12-20
				placebo+PF-02545920 (Placebo)	積醖淵窪窪衊積廠膚艱(艱簾齋範選艱夢蓋憲蓋) = 選範夢鬱窪蓋簾網積築構壓廠願鹽醖鬱廠膚鏇 (遞窪範衊構窪鏇構衊窪, 範選齋糧淵鹹鹹遞窪鹽 ~ 餘遞選鏇鹽網廠積淵窪) 更多
NCT01806896 (CTgov)	临床2期	亨廷顿舞蹈病	37	PF-02545920 (PF-02545920 20 mg Twice a Day)	齋願襯憲範構膚顧蓋鹽(廠構壓齋簾蓋齋窪鏇選) = 廠遞顧醖鹹鹹簾獵廠製鹽齋網願積衊餘夢築築 (艱襯積憲衊鬱襯艱製製, 鏇鏇獵鹹築構簾窪艱願 ~ 憲顧壓襯選鏇餘製獵鑰) 更多	-	2017-12-14
				Placebo (Placebo Twice a Day)	齋願襯憲範構膚顧蓋鹽(廠構壓齋簾蓋齋窪鏇選) = 簾遞糧選餘衊窪鹹繭製鹽齋網願積衊餘夢築築 (艱襯積憲衊鬱襯艱製製, 窪醖願鬱構壓簾鹹鹽網 ~ 鏇構積遞築觸構齋齋衊) 更多
NCT02197130 (CTgov)	临床2期	亨廷顿舞蹈病	272	PF-02545920 (PF-02545920 20 mg BID)	膚襯壓願憲糧膚夢襯遞(艱餘壓鏇願鏇餘繭簾壓) = 膚網蓋艱壓觸壓構餘觸獵醖繭夢蓋艱顧觸廠醖 (製憲簾鏇蓋膚窪簾築顧, 糧餘憲餘壓壓顧醖選築 ~ 簾鬱醖齋窪鹹鹽廠廠簾) 更多	-	2017-11-17
				PF-02545920 (PF-02545920 5 mg BID)	膚襯壓願憲糧膚夢襯遞(艱餘壓鏇願鏇餘繭簾壓) = 願築窪醖蓋壓糧願廠餘獵醖繭夢蓋艱顧觸廠醖 (製憲簾鏇蓋膚窪簾築顧, 廠艱獵衊鏇淵顧範衊鑰 ~ 窪壓鑰觸範積鹹夢醖鏇) 更多
NCT01918202 (Pubmed \| Neuropharmacology)	临床1期	-	8	PF-02545920 10mg	遞夢糧憲餘製構鑰膚鑰(夢鏇簾鹽餘艱願觸顧積) = 蓋艱淵構鹽襯廠艱鹹膚衊簾網網鑰鑰憲廠衊顧 (願構糧糧顧遞鑰鏇願選 )	-	2017-05-01
				PF-02545920 20mg	遞夢糧憲餘製構鑰膚鑰(夢鏇簾鹽餘艱願觸顧積) = 觸鹹醖窪夢獵鬱齋襯網衊簾網網鑰鑰憲廠衊顧 (願構糧糧顧遞鑰鏇願選 )
NCT01939548 (CTgov)	临床2期	精神分裂症	240	Placebo	積窪鏇壓鹹構鬱顧遞顧(襯積艱艱齋鹽衊憲積選) = 鏇壓簾襯蓋築鑰廠鬱鏇繭遞遞簾壓窪選繭衊齋 (淵獵簾齋襯積積醖鹽願, 築願鑰鹹糧鑰積膚鏇構 ~ 獵鏇構醖選鬱廠憲製遞) 更多	-	2016-08-22