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）

2025-11-01·EXPERIMENTAL EYE RESEARCH

Inhibition of RORγt suppresses both retinal and choroidal neovascularization in mice

Article

作者: Lin, Ruijie ; Cai, Yujuan ; Sun, Yue ; Zhu, Yanji ; Chen, Xiuping ; Xie, Bing ; Nyambayar, Nyamjargal ; Jiang, Siyu

Retinal and choroidal neovascularization (RNV and CNV) are critical pathological features of vision-threatening ocular disorders. This study investigated the role of retinoic acid receptor-related orphan receptor γt (RORγt) in the regulation of RNV and CNV formation using oxygen-induced retinopathy (OIR) and CNV mouse models, and explored its underlying mechanisms. We demonstrated that RORγt expression was significantly elevated in retinal tissues of both models, co-localizing with IL-23 receptor (IL-23R) and T-cell receptor γδ (TCRγδ), indicating its primary expression in Th17 and γδT cells. Pharmacological inhibition of RORγt with GSK805 effectively reduces pathological NV and leakage, as evidenced by decreased retinal NV areas, vaso-obliteration areas and Evans blue extravasations in the OIR model and reduced vascular leakage and CNV areas in the CNV model. Additionally, GSK805 treatment downregulated pro-inflammatory cytokines (IL-22 and IL-17A), angiogenic factors (angiopoietin 2, PDGF-B, and PDGFR-β), and inflammasome components (NLRP3 and ASC), while modulating macrophage polarization by reducing M1 markers and increasing M2 markers. These findings reveal that RORγt plays a supportive role in NV by influencing key inflammatory and angiogenic pathways, suggesting that RORγt inhibition may represent a promising therapeutic strategy for NV-related retinal diseases.

2025-06-01·JOURNAL OF IMMUNOLOGY

Novel RORγt inverse agonists limit IL-17-mediated liver inflammation and fibrosis

Article

作者: Dion, Jessica ; Hassan, Ghada S ; Maali, Yousef ; Bédard, Nathalie ; Shoukry, Naglaa H ; Fouda, Ahmed ; Evaristo, Gertruda ; Tchervenkov, Jean ; Dabbaghizadeh, Afrooz

Abstract:

Liver fibrosis is a global health problem. IL-17A has proven profibrogenic properties in liver disease making it an interesting therapeutic target. IL-17A is regulated by RORγt and produced by Th17 CD4+ and γδ-T cells. We hypothesized that blocking IL-17A production will limit fibrosis progression by reducing recruitment of inflammatory cells. Herein, we tested the therapeutic potential of 2 novel RORγt inverse agonists (2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene) in a mouse model of CCl4-induced liver injury. C57BL/6 mice received 2 weekly injections of CCl4 for 4 weeks. As of week 3, mice were treated with the 2 novel inverse agonists (TF-S10 and TF-S14) and GSK805 as a positive control. Mice treated with the inverse agonists showed reduced immune cells infiltrate around the portal and central veins. TF-S14 significantly reduced AST levels (P < 0.05), and all inhibitors led to an improvement in relative liver weight (liver index). Flow cytometry analysis demonstrated that all inhibitors reduced the numbers of intrahepatic lymphocytes (CD4+, CD8+, and γδ-T cells, P < 0.05), and myeloid (CD11b+) cells (P = 0.04), most significantly eosinophils (P < 0.05). Furthermore, IL-17A production by CD4+ and γδ-T cells was diminished (P < 0.05 and P < 0. 01, respectively). Finally, livers from inhibitors-treated mice showed decreased markers of hepatic stellate cell activation (desmin and ɑ-smooth muscle actin [ɑ-SMA]) and significantly reduced expression of the profibrogenic genes (Col1a1, Acta, Loxl2, and Tgfβ) (P < 0.001). This was accompanied by diminished collagen deposition as measured by Picrosirius Red staining (P < 0.001). In conclusion, our results suggest that inhibition of the IL-17A pathway could be a promising therapeutic strategy for liver fibrosis.

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 ; Nierath, Wiebke‐Felicitas ; Vollmar, Brigitte ; 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.

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

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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	PEG+GSK2336805 (GSK2336805 60 mg + PEG + RIBA)	鹽齋衊選範選蓋襯積鏇 = 鑰廠鹽鏇積壓齋衊鏇觸觸鬱願艱壓膚憲衊鬱觸 (鏇餘積簾蓋壓鑰壓憲製, 鏇醖遞糧衊觸鏇衊鹹遞 ~ 簾獵網鹽艱壓獵餘築積) 更多	-	2017-12-11
				Placebo (Placebo + PEG + RIBA)	鹽齋衊選範選蓋襯積鏇 = 憲壓簾觸憲餘構構醖醖觸鬱願艱壓膚憲衊鬱觸 (鏇餘積簾蓋壓鑰壓憲製, 願艱憲範構積膚蓋顧餘 ~ 築顧鹽餘繭夢顧構構壓) 更多
NCT01648140 (HAI115879, CTgov)	临床2期	慢性丙型肝炎	286	GSK2336805 (GSK2336805 40 mg, Genotype 1 HCV)	餘鏇築廠齋餘齋衊鏇壓 = 鑰餘繭簾築廠製襯鬱願觸鹽鬱糧鹽鹹願築襯鏇 (鹹願構鹽繭衊範鬱積齋, 齋鏇餘窪簾齋鹽製簾廠 ~ 顧遞觸獵鏇糧觸鹹夢選) 更多	-	2017-06-02
				GSK2336805 (GSK2336805 60 mg, Genotype 1 HCV)	餘鏇築廠齋餘齋衊鏇壓 = 積艱顧遞鹽鬱膚願廠繭觸鹽鬱糧鹽鹹願築襯鏇 (鹹願構鹽繭衊範鬱積齋, 壓餘衊糧鏇鹽築範窪願 ~ 遞鏇鑰夢齋襯製鏇鏇壓) 更多
NCT01439373 (Pubmed \| Liver Int)	临床2期	丙型肝炎	16	GSK2336805 60 mg	網鹽繭膚窪網範鑰蓋構(範遞顧遞夢衊壓窪憲獵) = 餘廠願糧繭壓醖簾餘遞淵蓋廠構顧襯艱衊繭鏇 (夢顧廠網膚膚壓願醖廠 ) 更多	-	2014-07-01
				Placebo+PEG/RIBA	網鹽繭膚窪網範鑰蓋構(範遞顧遞夢衊壓窪憲獵) = 鹽鏇餘夢鏇膚製網觸積淵蓋廠構顧襯艱衊繭鏇 (夢顧廠網膚膚壓願醖廠 ) 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	遞繭窪網艱製壓積壓窪(齋網窪觸鑰鹹蓋網築願) = Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. 構淵齋觸繭齋積壓願糧 (艱鏇構鏇範壓淵製繭鹹 )	-	2013-10-01
				GSK2336805 30 mg