A Two-part Trial to Evaluate the Safety, Tolerability, Clinical Effect and Systemic Exposure Potential of Topically Applied GSK2981278 Ointment in Subjects With Plaque Psoriasis

GSK2981278 is an inverse agonist of retinoic acid receptor-related orphan receptor (ROR) gamma. The aim of this study is to evaluate the safety, tolerability, clinical effect, and systemic exposure potential of topically applied GSK2981278 ointment in subjects with plaque psoriasis by treating all plaques on the body for 8 weeks. This single-center study will be conducted in two parts. Part A will be an open-label, single arm study and part B will be a double-blind, randomized, 2-arm, parallel-group, vehicle-controlled study. In Part A, 8 adult subjects and in Part B, 18 adult subjects with chronic stable plaque psoriasis will be enrolled. Total duration of study will be approximately 14 weeks. The results of this study will provide preliminary information about safety and efficacy of the drug and will help in providing the guidance for further development strategy.

开始日期2017-02-13

申办/合作机构

GSK Plc

EUCTR2016-002671-10-DE / Not yet recruiting临床1/2期

A two-part trial to evaluate the safety, tolerability, clinical effect and systemic exposure potential of topically applied GSK2981278 ointment in subjects with plaque psoriasis

开始日期2016-12-20

申办/合作机构

GlaxoSmithKline Research & Development Ltd.

NCT02548052 / Completed临床1期

A Phase I Trial to Evaluate Safety and Efficacy of Topically Applied GSK2981278 Ointment in a Psoriasis Plaque Test

GSK2981278 is a highly potent and selective inverse agonist of retinoic acid receptor-related orphan receptor gamma (ROR gamma) that is under development for topical treatment of plaque type psoriasis suitable for topical therapy.
This is the first study to administer GSK2981278 to subjects with psoriasis. This proof-of-concept study will evaluate the safety, tolerability and initial efficacy of a range of concentrations of GSK2981278 ointment with repeated topical applications in adult subjects with psoriasis. Results of this study will provide first clinical information on the drug's safety and efficacy in psoriasis and inform the selection of concentration of GSK2981278 ointment to be evaluated in subsequent clinical studies.
This is a Phase 1, single center, test field-randomized, vehicle- and positive- controlled, subject- and evaluator-blind study. All subjects will receive all 6 treatments on 6 test fields, for intra-individual treatment comparison. For every subject, the manner of assignment of each treatment to a particular test field will be according to a randomization scheme. Thus, the test fields within each subject, and not the subjects themselves, will be randomized.
The study will consist of screening, followed by a treatment period of 19 days, and a follow-up visit at Day 27 (+/-2) for subjects who will consent for biopsy. During the treatment period, subjects will receive all of these treatments: GSK2981278 ointment 0.03% weight by weight [w/w], 0.1% w/w, 0.8% w/w, 4% w/w, GSK2981278 vehicle, and betamethasone valerate 0.1% cream. The test fields on which these treatments will be applied will be identified on stable plaque(s) on the upper extremities, thighs and/or trunk. A blinded evaluator (an investigator or designee) will perform the measurements and assessments whereas an unblinded study staff member (not an evaluator) will perform biopsy collection.

开始日期2015-10-22

申办/合作机构

GSK Plc

100 项与 GSK-2981278A 相关的临床结果

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100 项与 GSK-2981278A 相关的转化医学

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100 项与 GSK-2981278A 相关的专利（医药）

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项与 GSK-2981278A 相关的文献（医药）

2025-01-01·BRAIN BEHAVIOR AND IMMUNITY

Double negative T cells promote surgery-induced neuroinflammation, microglial engulfment and cognitive dysfunction via the IL-17/CEBPβ/C3 pathway in adult mice

Article

作者: Chen, Ying ; Zou, Xin ; Xu, Ting ; Tin-Chun Wong, Gordon ; Xin, Wen-Jun ; Xin, Wenjun ; Liu, Jia-Xin ; Man-Tak Chu, John ; Liang, Zheng-Kai ; Feng, Xia ; Wei, Ming ; Duan, Yu-Juan

CD3(+) CD4(-) CD8(-) double negative T cells (DNTs) manifest themselves in autoimmune diseases and associated inflammation. In the central nervous system, the increased presence of DNTs is associated with the progression of neurological conditions and brain injury. Active DNTs that produce IL-17 have been regarded as a pro-inflammatory phenotype. The IL-17 signaling pathway mediates neuroinflammatory responses by inducing glial activation and producing inflammatory factors. Neuroinflammation is considered integral to the pathogenesis of perioperative neurocognitive disorders (PNDs), commonly developed after surgery in susceptible patients. We and others have demonstrated a significant role for complement C3 in surgery-induced neuroinflammation and cognitive impairment but the regulatory mechanisms for this remain unexplored. We hypothesized that surgery induces DNT infiltration into the CNS that in turn upregulates complement C3 expression and this causes changes that contribute to cognitive impairment. Using an adult murine abdominal surgery model, we investigated perioperative changes in cognitive performance, quantifying the presence of T cell subsets and phenotype, IL-17 signaling pathway activation, glial cell activation and C3 expression in the brain. Postoperative IL-17 specific inhibitor GSK2981278 administration or preoperatively conditional CEBPβ knock-down by AAV9 viral vector were then applied to evaluate the effect of inhibiting IL-17 signaling pathway on postoperative C3 expression and cognitive performance. The results showed an increased hippocampus infiltration of DNTs with augmented IL-17 production, along with C3 upregulation and cognitive impairment. Both inhibition of IL-17 or knock-down of CEBPβ significantly suppressed C3 expression, synaptic engulfment by microglia and attenuated cognitive impairment. These findings indicate that DNTs promote postoperative neuroinflammation and cognitive impairment via the IL-17/CEBPβ/C3 pathway and targeting this IL-17 axis could be a potential therapeutic strategy to ameliorate postoperative neuroinflammation and cognitive impairment.

2024-12-12·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Novel N-Sulfonamide-tetrahydroquinolines as Potent Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists for the Treatment of Psoriasis

Article

作者: Fu, Wei ; Li, Wei ; Chen, Baiyu ; Lv, Lunan ; Sun, Nannan ; Gao, Yang

Guided by the mode of action of 13, our previously discovered RORγt inverse agonist, we conducted five rounds of design syntheses and structure-activity relationship (SAR) studies, ultimately identifying RORγt inverse agonist 5a, which exhibited superior in vitro activity compared to 13. Besides, 5a showed promising therapeutic effects in alleviating psoriasis in mice by intraperitoneal injection. Due to the high lipophilicity and in vitro pharmacokinetic properties of 5a, it was formulated into an ointment, which enabled effective skin retention and mitigated systemic side effects. The ointment of 5a was assessed in the mouse model, where it demonstrated significant antipsoriatic effects, superior to 13 and comparable to the positive control GSK2981278, without obvious toxicity. Furthermore, we elucidated molecular mechanism of action for inverse agonist 5a and agonist 1e by means of molecular dynamics (MD) simulation. In summary, 5a holds great promise as a novel antipsoriatic drug candidate.

2024-12-01·BIOORGANIC CHEMISTRY

Discovery of novel and potent sulfonamide derivatives as orally available drug for psoriasis

Article

作者: Zhou, Xin-Ru ; Xu, Ran ; Sun, Shang-Shang ; Ping, Yi-Nuo ; Qi, Liang

The retinoid-related orphan receptor gamma-t (RORγt), a member of the nuclear receptor superfamily, functions as a ligand-dependent transcription factor. As a pivotal modulator in the development and functionality of T-helper 17 (Th17) cells, RORγt plays a crucial role in immune response regulation. Inverse agonists targeting RORγt demonstrate significant potential in modulating Th17 cell activity, offering a promising avenue for the development of therapeutics aimed at treating autoimmune diseases associated with Th17 dysregulation. GSK2981278 is a potent RORγt inverse agonist, but a drawback of GSK2981278 is its low pharmacokinetic profile, leading to a clinical failure. We have explored detailed structure-activity relationship of GSK2981278 trying to improve metabolic stability while maintaining RORγt activity. As a result, a novel series of sulfonamide derivatives was discovered as potent RORγt inverse agonists with improved drug-like properties. b14 had greatly improved In Vitro metabolic stability (T_1/2 = 36.2 min) compared to GSK2981278 (T_1/2 = 0.8 min). Oral dosing of compound b14 resulted in a dose-dependent suppression of IL-17A cytokine levels within a murine model of imiquimod-induced skin inflammation, underscoring its potential as a therapeutic intervention.

项与 GSK-2981278A 相关的新闻（医药）

2024-12-06

·微信

JMC | 复旦大学药学院付伟教授团队报道了用于银屑病治疗的新型RORγt反向激动剂

扫码报名2024肝病新药联盟年会暨减重新药论坛！近日，复旦大学药学院付伟教授团队在药物化学权威期刊Journal of Medicinal Chemistry上发表了题为“Discovery of Novel N-Sulfonamide-tetrahydroquinolines as Potent Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists for the Treatment of Psoriasis”的研究论文。通过五轮构效关系（SAR）的深入研究，成功发现了一种新型RORγt反向激动剂5a，为银屑病的治疗提供了新的潜在手段。银屑病是一种免疫介导的慢性炎症性皮肤病，研究表明白细胞介素-17（IL-17）在银屑病的发病机制中发挥着关键作用，而视黄酸受体相关孤儿受体γt（RORγt）作为转录因子，在调节IL-17相关基因的转录过程中起着至关重要的作用。因此，因此，研发有效且安全的RORγt反向激动剂是银屑病的潜在治疗手段。付伟教授团队通过基于结构的分子设计与构效关系研究，设计并合成了一系列N-磺酰胺-四氢喹啉类化合物，并从中筛选出了体外活性显著的化合物5a（IC50=0.094μM,max. inhibition=87.5%）。小鼠Th17细胞分化试验结果显示，化合物5a能够有效抑制小鼠Th17细胞的分化，其IC50为1.57 μM，最大抑制率达到95%。基于体外代谢稳定性研究和理化性质分析，研究团队进一步将化合物5a制成软膏剂型，并开展了皮肤滞留试验。通过将含有4%化合物5a的软膏制剂应用于猪耳皮肤的固定区域，并在12小时后进行评估，发现该软膏制剂的滞留率为4.36±0.97%，滞留量为15.50±3.3 μg，为保证局部持久的药效奠定物质基础。此外，小鼠涂抹4% 5a软膏后药-时曲线反映入血吸收较少，有利于减少潜在的系统性副作用。研究人员在咪喹莫德（IMQ）诱导的银屑病小鼠模型中，将三个不同剂量（4%、1%和0.25%）的5a软膏制剂涂抹在模型小鼠的右耳与背部皮肤，以评估化合物5a经皮给药的疗效。小鼠体内药效实验以皮质类固醇抗炎药Clobetasol和临床Ⅱ期RORγt反向激动剂GSK2981278作为阳性对照，通过游标卡尺测量右耳厚度，采用银屑病面积和严重指数（PASI）量化耳部与背部严重程度。研究结果显示，5a软膏治疗对小鼠体重不产生显著影响。5a在三个剂量下均展现出显著的抗炎效果，且存在明确的量效关系。4%剂量下5a效果最为突出，与GSK2981278疗效相当，且优于研究团队先前报道的化合物13。实验最后一天对小鼠耳朵和背部皮肤进行的组织学切片染色分析，证实5a有效地减少了炎症浸润，显著改善了小鼠皮肤状况。以上结果有力证实了5a在改善IMQ诱导的银屑病病变中的显著疗效。除了显著的疗效外，5a还表现出了良好的安全性。急性毒性实验结果显示，在12天内连续外用10%和20%的5a软膏制剂后，未见明显毒性反应。在hERG毒性评估实验中，5a对hERG通道的抑制作用较弱，其IC50值大于40 μM，比阳性对照Cisapride的IC50值高出700倍以上。此外，研究团队通过分子对接与分子动力学模拟等手段，深入阐明了5a作为RORγt反向激动剂的分子作用机制。通过建立反向激动剂5a结合体系、激动剂1e（SAR分析过程中发现）结合体系以及未结合配体的RORγt蛋白体系，经过比对分析，表明化合物5a的结合使得周围关键残基发生构象调整，尤其是Trp317和His479，进而破坏了残基His479、Tyr502和Phe506形成的"激动剂锁"以及H11、H11’和H12参与形成的疏水网络，最终导致H11、H11’和H12构象的不稳定，从而抑制共激活因子的招募。总之，复旦大学药学院付伟教授团队发现了一种用于银屑病治疗的新型RORγt反向激动剂5a。该化合物疗效显著、安全性好，4% 5a软膏制剂不仅展现出良好的皮肤滞留能力，而且能减少潜在的系统性副作用，为开发新型抗银屑病药物提供了有力候选。付伟教授复旦大学药学院教授、NASH新药联盟创始委员作为NASH新药联盟创始委员的付伟教授将受邀出席2024年12月13日～14日在上海举办的2024肝病新药联盟年会暨减重新药论坛。届时，她将以主持人的身份和与会嘉宾们共同探讨“医防合作、临床试验、出海策略及减重新药进展”，欢迎各位同药踊跃报名！扫码报名2024肝病新药联盟年会暨减重新药论坛！点击这里，报名参加行业盛会！

临床2期临床结果孤儿药

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-2981278A 相关的药物交易

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