A Phase 1, Double-blind, Placebo-controlled, Randomized, Single Ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of GSK2336805 (Part 1), Followed by an Open-label, Randomized, 4-way Crossover Study to Evaluate Short-term Safety, Tolerability and Pharmacokinetics of the Co-administration of TMC435 and GSK2336805 at Steady-state (Part 2), in Healthy Japanese Subjects

The purpose of the study is to investigate the safety, tolerability, and pharmacokinetic (what the body does to a medication) of GSK2336805 alone and with the co-administration of TMC435 in healthy Japanese participants.

开始日期2013-10-01

申办/合作机构

Johnson & Johnson (Ireland) Ltd.

NCT01827657

/ Completed临床1期

A Phase I, Open-Label, Parallel-Group, Two-Part Study to Evaluate the Pharmacokinetics and Safety of GSK2336805 in Subjects With Hepatic Impairment and Healthy Matched Control Subjects (HAI117380)

This is a single-dose, open-label, two part, parallel group study. This study is being conducted to determine the pharmacokinetics, safety and tolerability of GSK2336805 in subjects with varying degrees of hepatic impairment. Part 1 of the study will enroll subjects with mild and moderate hepatic impairment and healthy control subjects matched to the subjects in the moderate hepatic impairment category. The decision to commence Part 2 will be based on a review of the preliminary safety and pharmacokinetic data from subjects with moderate hepatic impairment. Part 2 will enroll subjects with severe hepatic impairment. Additionally, based on emergent data from Part 1, matched controls to the severe hepatic group may be enrolled (optional). Due to the potential difficulty in identifying eligible subjects with severe hepatic impairment, the study may be stopped prior to full enrollment in Part 2, provided that a minimum of 4 evaluable subjects with severe hepatic impairment have been enrolled. The study will consist of a Screening visit, a single dose Treatment Period and a Follow-up visit. Subjects will be screened for eligibility criteria within 30 days of enrolment. Subjects will be admitted to the clinical unit on Day -1; each subject will receive a single dose of GSK2336805 on Day 1 and will remain in the clinical unit for 5 days (check-out on Day 4). The follow-up visit will be conducted within 7-10 days after Day 1 dosing.

开始日期2013-05-28

申办/合作机构

GSK Plc

NCT01724086

/ Completed临床2期

A Phase IIa, Open-label Trial to Evaluate the Safety, Tolerability and Efficacy of a 12 Weeks Combination Therapy of TMC647055 and TMC435 With and Without GSK23336805 With a Pharmacokinetic Enhancer With and Without Ribavirin in Chronic Genotype 1 Hepatitis C Infected Patients

The purpose of this study is to explore the efficacy and safety of TMC647055, TMC435, and low-dose ritonavir, administered together with and without ribavirin and of TMC647055, TMC435, low-dose ritonavir administered together with GSK233680k without ribavirin in a limited number of patients with chronic hepatitis C virus (HCV) infection.

开始日期2012-10-01

申办/合作机构

Johnson & Johnson (Ireland) Ltd.

100 项与 GSK-805 相关的临床结果

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100 项与 GSK-805 相关的转化医学

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100 项与 GSK-805 相关的专利（医药）

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项与 GSK-805 相关的文献（医药）

2024-08-31·FASEB JOURNAL

GSK805 inhibits alpha‐smooth muscle expression and modulates liver inflammation without impairing the well‐being of mice

Article

作者: Zechner, Dietmar ; Bleich, André ; Reimann, Sabrina ; Leitner, Emily ; Vollmar, Brigitte ; Nierath, Wiebke‐Felicitas ; Hinz, Burkhard ; Schwarz, Rico

Abstract:

Cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell‐line LX‐2 and in vivo using male bile duct‐ligated BALB/c mice. In vitro, 0.3 μM GSK805 reduced alpha‐smooth muscle actin expression in LX‐2 cells. In vivo, GSK805 significantly decreased IL‐23R, TNF‐α, and IFN‐γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well‐being.

2023-10-01·Fish & shellfish immunology

Characterization of ccl20a.3 and ccl20l as gene markers for Th17 cell in turbot

Article

作者: Wang, Ying ; Yang, Dahai ; Wang, Wei ; Zhang, Yuanxing ; Chen, Weijie ; Liu, Qin

T-helper 17 lymphocytes (Th17) are the most common inflammatory cells identified in mammals. However, the identification of Th17 cells and the clarification of their function in teleost fish remain largely unknown. In this study, we took advantage of the single-cell RNA sequencing-based immune cell atlas that was identified in turbot (Scophthalmus maximus), and revealed two chemokine-related genes, ccl20a.3 and ccl20l, that were specifically expressed in Th17 cells. Moreover, through immuno-fluorescence analysis, we found that CCL20a.3 or CCL20l was co-expressed with the classical makers in Th17 cells, including IL17a/f1 and IL22. Furthermore, through a Th17 lineage-specific transcription factor RORc inhibitor GSK805 treatment, we found that the expression of ccl20a.3 and ccl20l was significantly impaired, compared with other T cell markers. Besides, we also found that ccl20a.3 and ccl20l exhibited the same dynamic response with the classical markers that were identified in Th17 cells during bacterial infection. Taken together, these results provide potential gene markers for better understanding of the dynamic immune responses of Th17 cells in teleost fish.

2022-12-01·Cell & bioscience3区 · 生物学

Ontogeny of RORγt+ cells in the intestine of newborns and its role in the development of experimental necrotizing enterocolitis

3区 · 生物学

ArticleOA

作者: Wang, Weifang ; Xu, Weijue ; Yi, Ruirong ; Yu, Mingcheng ; Wang, Yonghui ; Sheng, Qingfeng ; Lv, Zhibao ; Lu, Li ; Sun, Nannan ; Liang, Wenhua ; Luo, Lingjie ; Zhao, Xiuhao ; Pang, Jianfeng ; Wang, Feng

Abstract:

Background:

Neonates possess an immature and plastic immune system, which is a major cause of some diseases in newborns. Necrotizing enterocolitis (NEC) is a severe and devastating intestinal disease that typically affects premature infants. However, the development of intestinal immune cells in neonates and their roles in the pathological process of NEC have not been elucidated.

Results:

We examined the ontogeny of intestinal lamina propria lymphocytes in the early life of mice and found a high percentage of RORγt+ cells (containing inflammatory Th17 and ILC3 populations) during the first week of life. Importantly, the proportion of RORγt+ cells of intestinal lamina propria further increased in both NEC mice and patients tissue than the control. Furthermore, the application of GSK805, a specific antagonist of RORγt, inhibited IL-17A release and ameliorated NEC severity.

Conclusions:

Our data reveal the high proportion of RORγt+ cells in newborn mice may directly contribute to the development of NEC.

项与 GSK-805 相关的新闻（医药）

2024-11-21

·精准药物

靶点 RORγ 作用机制与药物分子研发进展

维甲酸受体相关孤儿受体（RORs，Retinoic acid receptor-related orphan receptors）属于核受体（NR）超家族的一个亚家族，作为转录调控因子发挥重要作用。ROR亚型包括RORα（NR1F1或RORa）、RORβ（NR1F2或RORb）、和RORγ（NR1F3或RORc）。RORγ作为RORγ1（也称为RORc1或RORγ）和RORγ2（也称为RORc2或RORγt）亚型存在，其中RORγ1在各种组织中广泛表达，而RORγt的表达局限于胸腺和免疫系统细胞。由于转录因子RORγt在分化IL-17产生T辅助细胞17（Th17）中的作用，与自身免疫密切相关（图1）。 IL-17 是一种促炎细胞因子，在炎症、自身免疫和宿主防御中起主导作用。在炎症部位，IL-17 刺激常驻细胞分泌趋化因子和其他促炎介质，从而将额外的炎症细胞募集到组织中。针对 IL-17 细胞因子本身或 IL-17 受体的单克隆抗体已证明在治疗银屑病、银屑病关节炎、和强直性脊柱炎等疾病具有临床疗效。IL-17 通路也与类风湿性关节炎等和多发性硬化症等免疫相关疾病有关。IL-17 由 T 细胞和其他免疫细胞的特定亚群产生，其中辅助性 T 细胞 17 （Th17）被认为在疾病发病机制中起主导作用。在这些细胞中，RORγt基因的免疫细胞特异性亚型表达，是 IL-17 表达和 Th17 细胞从初始 CD4+ T 细胞分化所必需的。因此，RORγt是一个非常很有前途的药物靶点，用于治疗自身免疫性疾病、病毒、代谢疾病、炎症、和癌症。此外，核受体靶向药物目前占美国和全球所有药品销售额的13%。 RORγ 结构由518个氨基酸组成，包括6个结构域（图2A，B）。与其他核受体类似，RORγ包含一个N端结构域(NTD，1−30 aa)，一个DNA结合域(DBD，31−95 aa)，一个铰链结构域(HD，96−265aa)，一个配体结合域(LBD，266−505aa)和一个C端结构域(CTD，506−518aa)。此外，在RORγ中，残基22−24是组氨酸、苏氨酸和丝氨酸，而在RORγt中，它们是蛋氨酸、精氨酸和苏氨酸（MRT）（图2B）。A/B区域被认为在DBD与DNA结合的特异性中发挥作用，但不直接与DNA相互作用。LBD可以与共激活物或辅抑制复合物相互作用，以调节基因转录；此外，通过LBD结构域可开发各种调节剂，包括激动剂、拮抗剂和反向激动剂。LBD 结构域还可以容纳变构配体。促进共激活因子复合物募集和增强基因转录的配体被称为受体激动剂（agonists）。一些甾醇配体已被报道为RORγ(t) 激动剂，包括24-脱氢胆固醇(desmosterol)、胆固醇和羟基胆固醇（图3）。代表性RORγ激动剂，如SR19355和LYC-55716(10.1021/acs.jmedchem.1c00731 )，后者已进入临床试验(针对肿瘤适应症)。拮抗剂是核受体调节的另一种药物形式，如GSK99324和SR-221127（图3）。RORγt抑制可影响与自身免疫性炎症性疾病相关的 IL-17、IL-22和粒细胞巨噬细胞集落刺激因子信号通路，如多发性硬化症、炎症性肠病、银屑病、类风湿关节炎（RA）、慢性阻塞性肺疾病和哮喘。此外，靶向 RORγt 还存在一类特殊的抑制剂。促进辅抑制因子复合物募集和减少基因转录的配体被称为反向激动剂（inverse agonists)。在药理学中是指和激动剂结合在相同的受体上，但引起相反的药理反应的分子。根据定义，反向激动剂的效能为负。反向激动剂的受体在没有结合任何配体必须有内在的基础活性。激动剂能增加其活性，而反向激动剂能降低其活性。沉默拮抗剂本身没有任何活性，但能阻止激动剂和反向激动剂的活性。这些反向激动剂表现出了有利的生物活性，包括对 RORγt 的强亲和力和抑制IL-17A细胞因子表达的能力（图3）。目前，已有许多有关 RORγt 反向激动剂的化学结构报道（图3），包括GSK2981278、GNE-3500、AZD-0284、VTP-43742、GSK805、T0901317和BMS-986251，其中一些开始临床试验。目前，除IMU-935（izumerogant，10.1002/cpdd.1243）外，其他反向激动剂，包括ABBV-157（cedirogant)和BI730357(bevurogant，10.1021/acsmedchemlett.0c00575）对银屑病不具有显著的临床疗效。 GSK2981278，设计用于局部给药，其生物利用度较低（10.1021/acs.jmedchem.8b00392）。然而，对具有合理的亲脂性和高代谢稳定性的化合物的描述是令人鼓舞的。为了提高其性能，对GSK2981278进行了大量的结构修改。Fauber等人通过磺胺基团引入脂肪族环，发现了GNE-3500（图4），它具有良好的效力、吸收、分布、代谢和排泄（ADME）。类似的研究有，通过优化取代核心结构和连接子。Liao等人通过保留磺胺基团并通过环化生成色烯环，阐明了RORγt 反向激动剂的高亲脂性（图4）。这些RORγt反向激动剂表现出与GSK2981278相似的结合模式；例如，分子的头部基团被插入“激动剂锁（agonist lock）”附近的疏水口袋，包括W317、L324、M358、L362、L391、L396和I400，尾部结构与R367相互作用，与“硫酸盐口袋”形成氢键相互作用。最近，Sun 等人通过环化技术设计并合成了苯并四氢喹啉衍生物（10.1021/acs.jmedchem.4c01727），该候选化合物（(R)-D4）具有可口服的优化药代动力学特性、和在临床前动物模型（皮炎、关节炎等）中具有体内活性。然而，RORγt靶向药物的临床试验一直受到高失败率的困扰，主要是因为缺乏疗效（外用）或安全信号（口服）。胸腺细胞异常的风险已经被多次报道，已经停止开发的BMS-986251或诺华开发的潜在临床候选药物。减轻这些风险的可能性可能涉及使用具有化学、不干扰胸腺细胞成熟的结构的RORγt反向激动剂。此外，还有最近受到关注的蛋白降解剂。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

孤儿药临床结果信使RNA

100 项与 GSK-805 相关的药物交易

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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
慢性丙型肝炎	临床2期	美国	GSK Plc	2011-07-07
慢性丙型肝炎	临床2期	波多黎各	GSK Plc	2011-07-07
慢性丙型肝炎基因型 1	临床1期	美国	GSK Plc	2010-11-03

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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


NCT01439373 (CTgov)	临床2期	慢性丙型肝炎	16	RIBA+PEG+GSK2336805 (GSK2336805 60 mg + PEG + RIBA)	蓋艱膚鑰築糧顧衊構壓 = 窪衊衊襯選壓膚齋築醖構膚蓋夢膚夢窪齋淵艱 (製簾窪網積餘餘衊憲餘, 憲鹽憲鏇鑰齋繭遞壓遞 ~ 遞製範鑰鹽醖壓夢製廠) 更多	-	2017-12-11
				Placebo+PEG (Placebo + PEG + RIBA)	蓋艱膚鑰築糧顧衊構壓 = 膚範衊願襯築鑰廠淵範構膚蓋夢膚夢窪齋淵艱 (製簾窪網積餘餘衊憲餘, 衊淵壓蓋壓衊製鑰網簾 ~ 夢選網構願膚艱築鏇膚) 更多
NCT01648140 (HAI115879, CTgov)	临床2期	慢性丙型肝炎	286	GSK2336805 (GSK2336805 40 mg, Genotype 1 HCV)	繭築鹽窪襯齋夢鹽願觸 = 窪願觸淵獵廠壓鹹選膚鬱糧襯製獵憲鹽積齋窪 (遞積夢襯遞餘築艱觸憲, 淵選廠範廠餘願鏇鬱糧 ~ 網廠鑰蓋範膚糧廠蓋齋) 更多	-	2017-06-02
				GSK2336805 (GSK2336805 60 mg, Genotype 1 HCV)	繭築鹽窪襯齋夢鹽願觸 = 衊鬱鹹觸鑰膚構襯鹽網鬱糧襯製獵憲鹽積齋窪 (遞積夢襯遞餘築艱觸憲, 積簾憲窪構獵蓋遞蓋壓 ~ 淵衊遞選獵齋艱顧壓構) 更多
NCT01439373 (Pubmed \| Liver Int)	临床2期	丙型肝炎	16	GSK2336805 60 mg	襯範醖齋範鬱構淵鹽醖(醖憲醖襯鬱積蓋鏇糧鹹) = 淵築構願選廠蓋簾襯憲衊廠襯鬱簾遞構願選醖 (鬱壓顧膚齋膚網築顧艱 ) 更多	-	2014-07-01
				Placebo+PEG/RIBA	襯範醖齋範鬱構淵鹽醖(醖憲醖襯鬱積蓋鏇糧鹹) = 鏇鑰淵夢廠簾鏇艱顧積衊廠襯鬱簾遞構願選醖 (鬱壓顧膚齋膚網築顧艱 ) 更多
NCT01277692 (Pubmed \| Antimicrob Agents Chemother)	临床1期	慢性丙型肝炎基因型 1	69	GSK2336805 10 mg	艱觸淵顧選憲鏇遞簾顧(獵醖齋顧醖獵繭獵糧襯) = Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. 窪醖鹹艱鹽獵積遞獵鹽 (願蓋積糧願製觸齋齋獵 )	-	2013-10-01
				GSK2336805 30 mg