SRT-2104(SRT-2104) - 药物靶点：SIRT1_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

SIRT1

作用机制

SIRT1刺激剂(NAD依赖性脱乙酰酶sirtuin-1刺激剂)

治疗领域

免疫系统疾病心血管疾病内分泌与代谢疾病+ [6]

在研适应症-

非在研适应症

溃疡性结肠炎2型糖尿病短暂性脑缺血发作+ [6]

原研机构

GSK Plc

在研机构-

非在研机构

Sirtris Pharmaceuticals, Inc.

GSK Plc

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-

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结构

分子式C26H24N6O2S2

InChIKeyLAMQVIQMVKWXOC-UHFFFAOYSA-N

CAS号1093403-33-8

关联

21

项与 SRT-2104 相关的临床试验

NCT01702493 / Completed临床1期

A Phase 1, Open-Label, Randomized, Controlled, Four-Period Crossover Study to Assess the Relative Bioavailability of New Oral Formulations of SRT2104 in Healthy Male Volunteers

This is an open-label, randomized, controlled, single center study to assess the safety, variability in exposure, and relative bioavailability of new oral formulations of SRT2104. This is a two part study and each part consists of screening (within 21 days of the first scheduled dose of SRT2104), treatment period and follow-up visit (approximately 6 days after the last dose). Part 1: Subjects will receive all four fomulations of SRT2104 and their order of their doses will be randomized. Each subject will receive one formulation as a 500 milligram (mg) dose (in the form of two 250 mg capsules or tablets) in each session given in the fasted state. Each dose will be separated by at least 6 days. Pharmacokinetic (PK) sampling will be done pre and post each scheduled dosing session. After all 4 dosing sessions, the safety and PK data will be reviewed to determine which, if any, formulation(s) will be carried forward into Part 2. The total duration will be approximately 7 weeks. Part 2: Is further divided into Part 2A, 2B and 2C of the study and are optional. After the completion of Part 1, the sponsor will decide whether to proceed with any or all of Part 2, and whether the selected formulation(s) is to be administered in the fed or fasted state for Parts 2B and 2C. For all the sub parts of Part 2 the pre and post-dose PK samples will be obtained. Part 2A: A single-dose of the selected formulation(s) from Part 1 will be administered after a standard meal to assess the effect of food on the bioavailability of SRT2104 at the 500 mg dose. The total duration will be approximately 4 weeks. Part 2B: A single alternative dose (other than 500 mg, but not to exceed 2000 mg) of the selected formulation(s) from Part 1 will be administered to assess the safety and PK profile of this dose level. The total duration will be approximately 4 weeks. Part 2C: The selected formulation(s) from Part 1 will be administered at the 500 mg dose once daily for 7 consecutive days, to assess the safety and tolerability and characterize the PK profile of repeat dosing. The total duration will be approximately 5 weeks.

开始日期2012-10-30

申办/合作机构

Sirtris Pharmaceuticals, Inc.

NCT01453491 / Completed临床1期

A Phase 1b, Exploratory Study to Assess the Safety, Tolerability, Colonic Tissue Exposure, and Anti-Inflammatory Effects of Two Different Doses of SRT2104 in Subjects With Mild to Moderate Ulcerative Colitis

The purpose of this research study is to:
1) Test the safety and tolerability of 2 different oral doses of SRT2104 in subjects with ulcerative colitis
2) Determine the amount of SRT2104 measured from a single blood sample in addition to colon and/or rectal tissue samples (biopsies)
3) Determine whether SRT2104 has any anti-inflammatory effect on the colon and/or rectum when taken orally for 8 weeks
4) Determine whether SRT2104 causes any detectable changes to specific biomarkers. A biomarker is a biological marker (or substance such as a protein) that is used as an indicator of changes in a biological state that corresponds to the risk or progression of a disease.

开始日期2012-02-13

申办/合作机构

Sirtris Pharmaceuticals, Inc.

[+1]

NCT01039909 / Withdrawn临床1期

A Phase I, Randomized, Double-Blind, Placebo-Controlled, Clinical Study to Assess the Effects of SRT2104 Upon Immobilization-Induced Skeletal Muscle Atrophy in Healthy Human Volunteers

The main purpose of this study is to investigate the effect of SRT2104 upon energy production in muscle (specifically the maximum amount of energy produced with muscle contraction), how much sugar and fat are stored in the muscle, and the size of the muscle after receiving 2.0 g of SRT2104 or placebo given in capsule form once a day for 28 days including a 14 day knee and lower leg immobilisation period during the final 14 days of dosing.
Imaging methods, muscle biopsies and exercise tests will be used in the study to see whether the following measurements change after taking SRT2104 for 28 days, including an immobilised knee and lower leg for the final 14 days of dosing.
i) energy reaching the muscles ii) muscle strength iii) changes in the structure of the muscle
This study will also investigate the pharmacokinetics, safety and tolerability of 2.0 g of SRT2104 administered orally once daily for 28 consecutive days. The investigation of pharmacokinetics of SRT2104 allows us to gather information regarding:
i) how long it takes for the drug to be absorbed and detected in the blood ii) how much we can detect iii) how long we can detect it for iv) how often we need to give the drug to maintain a steady amount in the blood.
SRT2104 will be given to healthy subjects aged between 18 and 40 years old. Subjects will participate in this single centre study for approximately 79 days. The study consists of 11 outpatient clinic visits and 4 telephone calls (including a prescreen call to determine whether subjects are interested in participating).

开始日期2011-01-01

申办/合作机构

GSK Plc

100 项与 SRT-2104 相关的临床结果

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100 项与 SRT-2104 相关的转化医学

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100 项与 SRT-2104 相关的专利（医药）

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55

项与 SRT-2104 相关的文献（医药）

2024-12-01·International Immunopharmacology

Small molecule SIRT1 activators counteract oxidative stress-induced inflammasome activation and nucleolar stress in retinal degeneration

Article

作者: Li, Mengyao ; Li, Haiming ; Xu, Qian ; Zhang, Yu ; Fan, Qian ; Qu, Yi ; Jiang, Fan

BACKGROUNDThe nicotinamide adenosine dinucleotide-dependent deacetylase Sirtuin 1 (SIRT1) has been identified as a protective factor that inhibits the activation of nucleotide-binding and oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. However, whether pharmacological SIRT1 activators can protect retinal pigment epithelial (RPE) cells against oxidative and inflammatory injuries related to age-related macular degeneration remains to be explored.METHODSTwo small molecule specific SIRT1 activators (SRT2104 and CAY10602) were tested, with resveratrol being used as a positive control. Mouse models with sodium iodate-induced retinal degeneration were constructed. ARPE-19 cells in culture were used for in vitro experiments. The effects of SIRT1 activators on H₂O₂-induced ARPE-19 cell injury were determined by reactive oxygen species quantification, western blotting, flow cytometry and immunofluorescence staining. In vivo, the severity of retinal damage was assessed using flash electroretinography and histopathological analysis.RESULTSIn vitro, SRT2104, CAY10602 and resveratrol significantly attenuated H₂O₂-induced cell death, nucleolar stress response, and reactive oxygen species accumulation. In H₂O₂-stimulated cells, SIRT1 activators reduced the level of NLRP3, inhibited the activation of caspase-1, and decreased the production of interleukin (IL)-1β and IL-18. The inhibitory effects of SIRT1 activators on caspase-1 activation and IL-1β production were blunted by SIRT1 gene silencing. In vivo, treatment with SRT2104 or CAY10602 in mice with sodium iodate-induced retinal degeneration markedly improved the retinal functions and reduced the loss of RPE cells.CONCLUSIONOur study suggests that small molecule SIRT1 activators are effective for protection of RPE cells against oxidative stress-induced NLRP3 inflammasome activation, highlighting potential applications in the treatment of macular degeneration associated RPE dysfunctions.

2024-12-01·Ageing Research Reviews

The role of sirtuin 1 in ageing and neurodegenerative disease: A molecular perspective

Review

作者: Kumar, Gaurav ; Alzarea, Sami I. ; Hassan Almalki, Waleed ; Bhat, Asif Ahmad ; Afzal, Muhammad ; Singh, Sachin Kumar ; Pant, Kumud ; Kazmi, Imran ; Singh, Thakur Gurjeet ; Alzarea, Sami I ; pant, Kumud ; Hassan almalki, Waleed ; Gupta, Gaurav ; Ali, Haider ; Thapa, Riya ; Moglad, Ehssan

Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, has emerged as a key regulator of cellular processes linked to ageing and neurodegeneration. SIRT1 modulates various signalling pathways, including those involved in autophagy, oxidative stress, and mitochondrial function, which are critical in the pathogenesis of neurodegenerative diseases. This review explores the therapeutic potential of SIRT1 in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Preclinical studies have demonstrated that SIRT1 activators, such as resveratrol, SRT1720, and SRT2104, can alleviate disease symptoms by reducing oxidative stress, enhancing autophagic flux, and promoting neuronal survival. Ongoing clinical trials are evaluating the efficacy of these SIRT1 activators, providing hope for future therapeutic strategies targeting SIRT1 in neurodegenerative diseases. This review explores the role of SIRT1 in ageing and neurodegenerative diseases, with a particular focus on its molecular mechanisms, therapeutic potential, and clinical applications.

2024-10-01·Journal of Dairy Science

Unveiling the regulatory role of SIRT1 in the oxidative stress response of bovine mammary cells

Article

作者: Liu, Juxiong ; Hu, Guiqiu ; Cao, Yu ; Zhang, Yufei ; Guo, Wenjin ; Hu, Huijie ; Liu, Shu ; Fu, Shoupeng ; Yuan, Shuai ; Zhang, Meng

High-yield dairy cows typically undergo intense cellular metabolism, leading to oxidative stress in their mammary tissues. Our study found that compared with ordinary cows, these high-yield cows had significantly elevated levels of H₂O₂, lipoperoxidase, and total antioxidant capacity in their blood. This increased oxidative stress is associated with heightened expression of genes such as GCLC, GCLM, and SIRT1 and proteins such as SIRT1 in the mammary tissue of high-yield cows. We stimulated MAC-T cells with H₂O₂ at a concentration equal to the average H₂O₂ level in the serum of ethically high-yielding cows, as detected by an assay kit. Our observations revealed that short-term exposure (12 h) to H₂O₂ upregulated the expression of the SIRT1 gene and SIRT1 protein. It also increased gene expression for SOD2, CAT, GCLC, GCLM, PGC-1α, and NQO1, elevated the phosphorylation of AMPK, and enhanced protein expression of PGC-1α, NQO1, Nrf2, and HO-1, as well as reduced the phosphorylation of NF-κB. Additionally, short-term H₂O₂ stimulation resulted in increased total antioxidant capacity and levels of superoxide dismutase, glutathione, and catalase in the mammary epithelial cells of dairy cows. In contrast, prolonged exposure to H₂O₂ (24 h) yielded opposite results, indicating reduced antioxidant capacity. Further investigation showed that the SIRT1 inhibitor EX 527 could reverse the enhanced cellular antioxidant capacity triggered by short-term oxidative stress. However, it is crucial to note that although 12 h of H₂O₂ stimulation improved antioxidant capacity, reactive oxygen species (ROS) and malondialdehyde (MDA) levels inside the cell gradually increased over time, suggesting greater damage under long-term stimulation. Conversely, the SIRT1 activator SRT 2104 could reverse the reduced cellular antioxidant capacity caused by long-term oxidative stress and significantly inhibit the accumulation of ROS and MDA. Notably, SRT 2104 demonstrated similar effects in MAC-T cells during lactation. In summary, SIRT1 plays a crucial role in regulating the antioxidant capacity of mammary epithelial cells in dairy cows. This discovery provides valuable insights into the antioxidant mechanisms of mammary cells, which can serve as a theoretical foundation for future mammary health strategies.

100 项与 SRT-2104 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12186

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
2型糖尿病	申请上市	波兰	GSK Plc	2009-08-19
斑块状银屑病	临床2期	美国	GSK Plc	2010-06-07
2型糖尿病	临床2期	爱沙尼亚	GSK Plc	2009-08-19
2型糖尿病	临床2期	英国	GSK Plc	2009-08-19
2型糖尿病	临床2期	匈牙利	GSK Plc	2009-08-19
2型糖尿病	临床2期	俄罗斯	GSK Plc	2009-08-19
2型糖尿病	临床2期	保加利亚	GSK Plc	2009-08-19
2型糖尿病	临床2期	乌克兰	GSK Plc	2009-08-19
2型糖尿病	临床2期	罗马尼亚	GSK Plc	2009-08-19
慢性阻塞性肺疾病	临床2期	英国	GSK Plc	2009-04-06

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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


NCT00937326 (CTgov)	临床2期	2型糖尿病	227	Placebo	襯餘範構餘衊糧遞鏇顧(蓋壓願鏇獵顧鬱獵構築) = 觸顧膚憲艱膚鹽襯襯蓋觸遞鏇鹽鏇鑰鹽簾製糧 (淵鏇願窪築積夢遞糧淵, 選鹹願糧壓網獵壓窪簾 ~ 窪襯餘遞築範窪範夢鑰) 更多	-	2018-04-09
NCT01031108 (Pubmed)	临床1期	2型糖尿病	15	SRT2104	鹹範廠願蓋鬱遞醖獵鹹(艱簾觸夢網觸蓋餘衊淵) = 醖廠齋壓淵襯繭範醖網獵築觸廠襯鹽蓋繭衊築 (鹽觸鬱築鏇獵積衊膚鏇 )	-	2017-01-01
				Placebo	(壓衊膚膚廠製鏇鏇鹽淵) = 遞範製鬱觸齋築鹹鹹餘鑰構壓糧醖醖窪齋鑰鹹 (壓築網壓膚壓餘鹽淵廠 )
NCT01014117 (Pubmed \| Crit Care Med)	临床1期	-	41	SRT2104 pretreatment for 7 days (2 g/d)	範膚糧築繭網繭餘憲蓋(糧憲簾艱鑰鑰簾膚餘糧) = 夢顧衊鑰夢淵顧蓋鹹範鏇網餘醖衊積淵網顧積 (積顧淵觸夢鬱製觸壓築 )	-	2015-06-01
				Single SRT2104 dose (2 g) pretreatment	範膚糧築繭網繭餘憲蓋(糧憲簾艱鑰鑰簾膚餘糧) = 積廠艱範齋齋醖簾夢築鏇網餘醖衊積淵網顧積 (積顧淵觸夢鬱製觸壓築 )
NCT01031108 (Pubmed \| J Am Heart Assoc)	临床1期	吸纸烟	38	SRT2104	鏇淵範淵醖鑰憲鬱選構(糧簾顧憲顧顧憲衊製遞) = 窪簾憲觸醖廠淵觸醖齋壓襯鹽範製繭範獵淵簾 (簾繭廠餘餘醖齋觸築構 ) 更多	-	2013-06-14
				Placebo	鏇淵範淵醖鑰憲鬱選構(糧簾顧憲顧顧憲衊製遞) = 衊網顧廠製蓋鹹廠蓋襯壓襯鹽範製繭範獵淵簾 (簾繭廠餘餘醖齋觸築構 ) 更多