(Ethynylcytidine) - 药物靶点：CTPS x POLR1A x POLR2A x Ribonucleotide reductase_专利_临床

概要

基本信息

药物类型

小分子化药

别名

3'-C-Ethynylcytidine、4-Amino-1-((2R,3R,4R,5R)-4-ethynyl-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)pyrimidin-2-one、ECyd

+ [4]

靶点

CTPS x POLR1A x POLR2A x Ribonucleotide reductase

作用机制

CTPS抑制剂(胞嘧啶三磷酸合成酶抑制剂)、POLR1A抑制剂(DNA指导的RNA聚合酶I-RPA1亚基抑制剂)、POLR2A抑制剂(DNA指导的RNA聚合酶II-RPB1亚基抑制剂)

+ [1]

治疗领域

肿瘤

在研适应症-

非在研适应症

头颈癌转移头颈部肿瘤

原研机构

Taiho Pharmaceutical Co., Ltd.

在研机构-

非在研机构

Taiho Pharmaceutical Co., Ltd.

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C11H13N3O5

InChIKeyJFIWEPHGRUDAJN-DYUFWOLASA-N

CAS号180300-43-0

关联

2

项与 Ethynylcytidine 相关的临床试验

NCT00737360 / Terminated临床2期

Phase II Study of TAS-106 in Patients With Recurrent or Metastatic Head and Neck Cancer Refractory to Platinum Based Chemotherapy

The purpose of this study is to determine whether TAS-106 is effective to patients with recurrent or metastatic head and neck cancer refractory to platinum based chemotherapy.

开始日期2008-08-01

申办/合作机构

Taiho Pharmaceutical Co., Ltd.

NCT00752011 / Completed临床1期IIT

Phase I Dose Escalating Study Of Tas-106 In Combination With Carboplatin In Patients With Solid Tumors

The goal of this clinical research study is to find the highest safe dose of the combination of TAS-106 and carboplatin that can be given to patients with advanced cancer or cancer that has spread.
Objectives:
Primary Objectives:
To determine the maximum tolerated dose (MTD) of the combination of TAS-106 and carboplatin administered by intravenous infusion every 3 weeks.
To perform Pharmacokinetic (PK) analysis of TAS-106 and carboplatin
Secondary objectives:
To assess the antitumor activity of TAS-106 combined with carboplatin
To investigate the relationship between selected biomarkers and efficacy and safety outcomes.

开始日期2008-06-01

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

100 项与 Ethynylcytidine 相关的临床结果

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100 项与 Ethynylcytidine 相关的转化医学

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100 项与 Ethynylcytidine 相关的专利（医药）

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75

项与 Ethynylcytidine 相关的文献（医药）

2023-06-13·Journal of Biomolecular Structure and Dynamics

Combined machine learning and pharmacophore based virtual screening approaches to screen for antibiofilm inhibitors targeting LasR of Pseudomonas aeruginosa

Article

作者: Ramasamy, Monica ; Senthil, Kalaiselvi ; Ramasamy, Janani ; Murugesan, Rajeswari ; Vetrivel, Aishwarya ; Natchimuthu, Santhi

Pseudomonas aeruginosa, a virulent pathogen affects patients with cystic fibrosis and nosocomial infections. Quorum sensing (QS) mechanism plays a crucial role in causing these ailments by mediating biofilm formation and expressing virulent genes. A novel approach to circumvent this bacterial infection is by hindering its QS network. Targeting LasR of las system serves beneficial as it holds the top position in QS system cascade. Here, we have integrated machine learning, pharmacophore based virtual screening, molecular docking and simulation studies to look for new leads as inhibitors for LasR. Support vector machine (SVM) learning algorithm was used to generate QSAR models from 66 antagonist dataset. The top three models resulted in correlation coefficient (R²) values of 0.67, 0.86, and 0.91, respectively. The correlation coefficient (R²_test) values on external test set were found to be 0.62, 0.57, and 0.55, respectively. A four-point pharmacophore model was developed. The pharmacophore hypothesis AAAD_1 was used to screen for potential leads against MolPort database in ZincPharmer. The leads which showed predicted pIC50 value of >8.00 by SVM models were subjected to docking analysis that reranked the compounds based on docking scores. Four top leads namely ZINC3851967 N-[3,5-bis(trifluoromethyl)phenyl]-5-tert-butyl-6-chloropyrazine-2-carboxamide, ZINC4024175 4-Amino-1-[(2R,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidine-5-carbonitrile, ZINC2125703 N-[(5-Methoxy-4,7-dimethyl-2-oxo-2H-chromen-3-yl)acetyl]-beta-alanine, and ZINC3851966 N-[3,5-Bis(trifluoromethyl)phenyl]5-tert-butylpyrazine-2-carboxamide were selected. These compounds were checked for its stability by performing a molecular dynamics simulation for a period of 100 ns. The ADME properties of the leads were also determined. Hence, the compounds identified in this study can be used as possible leads for developing a novel inhibitor for LasR.Communicated by Ramaswamy H. Sarma.

2020-08-01·Bioorganic & Medicinal Chemistry Letters4区 · 医学

Synthesis and biological evaluation of thioadatanserin and its dialkylated products as partial 5-HTR1A agonists and 5-HTR2A antagonists for potential use in depression and anxiety disorders

4区 · 医学

Article

作者: Siegler, Maxime A ; Baradaran-Noviri, Sarah ; Zuluaga, Andrea ; Vasquez Matute, Diego ; Evans, Colleen A ; Perez-Cervantes, Natalia

Thionation of adatanserin hydrochloride (2) with Lawesson's reagent in toluene/triethylamine afforded novel compound, (3r,5r,7r)-N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)adamantane-1-carbothioamide (thioadatanserin, 3) in 84-90% isolated yield. Thioadatanserin underwent a tandem double alkylation with methyl iodide and benzyl bromide in NaH/THF to produce novel dialkylated products 6 and 7 respectively. The single X-ray crystal structure of 7 was determined to be 1-(2-((E- ((3r,5r,7r)-adamantan-1-yl)benzylthio)methylene)amino)ethyl)-1-benzyl-4- (pyrimidin-2-yl)piperazin-1-ium bromide showing that the piperazine ring adopts a chair-like configuration that is not co-planar with the pyrimidine ring. Thioadatanserin emerged as a dual potent partial agonist with activity against 5-HTR_1A (EC₅₀ 6.7 nM) and antagonist activity against 5-HTR_2A (IC₅₀ 62.3 nM) and was selective over 5-HTR_2C receptor (IC₅₀ > 3333 nM) in the PathHunter® β-arrestin assays.

2018-03-01·Neurochemical Research3区 · 医学

2R,4R-APDC, a Metabotropic Glutamate Receptor Agonist, Reduced Neuronal Apoptosis by Upregulating MicroRNA-128 in a Rat Model After Seizures

3区 · 医学

Article

作者: Han, Yu-Xiang ; Lin, You-Ting ; Xu, Jing-Jing ; Yao, Hong ; Xue, Yuan ; Pang, Yue-Jiu ; Feng, Ya-Bo

This study aimed to study the protective effect of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), a selective metabotropic glutamate receptor agonist, against hippocampal neuronal apoptosis induced by seizures in a rat model of pilocarpine-induced epilepsy. The Morris water maze test was used to assess the spatial memory abilities of epileptic rats with or without 2R,4R-APDC treatment. TUNEL assay was performed to examine neuronal apoptosis in hippocampus. Western blot was conducted to evaluate changes in the levels of caspase-3 and caspase-9 in hippocampus. Real-time PCR was used to determine the levels of microRNA-128 (miR-128) in hippocampus. The results of the Morris water maze test showed that the 2R,4R-APDC treatment reduced the escape latencies and swimming lengths of rats after seizures. The TUNEL assay showed that 2R,4R-APDC significantly counteracted seizure-induced cell apoptosis. The western blot confirmed this finding, demonstrating that the levels of cleaved caspase-3 and cleaved caspase-9 were potently decreased by 2R,4R-APDC in rat hippocampus after seizures. In addition, 2R,4R-APDC upregulated miR-128 expression levels in the hippocampus. A miR-128 mimic or inhibitor decreased or increased the percentage of TUNEL-positive cells in rats after seizures and 2R,4R-APDC treatment, respectively. The levels of both cleaved caspase-3 and cleaved caspase-9 were decreased in hippocampus exposed to the miR-128 mimic, whereas they were markedly increased in miR-128 inhibitor-treated hippocampus. In conclusion, 2R,4R-APDC protected hippocampal cells from cell apoptosis after seizures, possibly by upregulating miR-128.

100 项与 Ethynylcytidine 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06656

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
头颈癌转移	临床2期	中国香港	Taiho Pharmaceutical Co., Ltd.	2008-08-01
头颈癌转移	临床2期	新加坡	Taiho Pharmaceutical Co., Ltd.	2008-08-01
头颈癌转移	临床2期	美国	Taiho Pharmaceutical Co., Ltd.	2008-08-01
头颈癌转移	临床2期	中国台湾	Taiho Pharmaceutical Co., Ltd.	2008-08-01
头颈部肿瘤	临床2期	中国台湾	Taiho Pharmaceutical Co., Ltd.	2008-08-01
头颈部肿瘤	临床2期	新加坡	Taiho Pharmaceutical Co., Ltd.	2008-08-01
头颈部肿瘤	临床2期	美国	Taiho Pharmaceutical Co., Ltd.	2008-08-01
头颈部肿瘤	临床2期	中国香港	Taiho Pharmaceutical Co., Ltd.	2008-08-01

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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


ASCO2007	临床1期	实体瘤	18	TAS-106	(艱鏇選選鏇簾夢窪齋鹽) = 憲鹽觸膚襯襯壓繭鬱廠蓋顧糧廠鬱衊範繭壓鑰 (齋艱艱鏇夢糧選憲獵顧 )	-	2007-06-20
ASCO2007	临床1期	实体瘤	33	TAS-106	(窪艱獵鑰鏇憲憲齋獵艱) = 築艱繭遞齋襯淵構積齋觸廠廠顧憲壓餘鬱醖餘 (蓋壓築選衊糧觸顧壓鏇 ) 更多	-	2007-06-20