A Multicenter, Vehicle-controlled, Double-Masked, Randomized Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Exploratory Efficacy of AGN-242428 and AGN-231868 in Participants With Dry Eye Disease

This will be a 2 stage study in which Stage 1 will evaluate the safety of AGN-242428 and AGN-231868, how well they are tolerated and how they move through the body when administered. After the sponsor's determination of adequate safety and tolerability of the interventions in Stage 1, Stage 2 will begin. Stage 2 will also evaluate the safety and tolerability of AGN-242428 and AGN-231868, how effective they are in treating dry eye disease and assess the plasma and tear exposure of both ophthalmic solutions.

开始日期2020-03-04

申办/合作机构

Allergan Ltd. (Ireland)

NCT03339999 / Terminated临床2期

A Randomized, Double-Blind, Placebo-Controlled, Study to Assess the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of AGN-242428 in Patients With Plaque Psoriasis

The purpose of this study is to evaluate the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of 3 doses of AGN-242428 in adult participants with moderate to severe plaque-type psoriasis.

开始日期2017-11-15

申办/合作机构

Vitae Pharmaceuticals LLC

NCT02555709 / Completed临床1/2期

A Randomized, Double-Blind, Placebo-Controlled Ascending Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VTP-43742 in Healthy Volunteers and Psoriatic Patients and Clinical Proof-of-Concept in Psoriatic Patients

This is a two-part, randomized, double-blind, placebo-controlled study in which VTP-43742 will be administered to normal healthy volunteers (NHV) and to moderate to severe psoriatic patients, both in sequential ascending dose panels.

开始日期2015-08-01

申办/合作机构

Vitae Pharmaceuticals LLC

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项与 Vimirogant 相关的文献（医药）

2022-08-01·Pharmacological research

Nuclear receptor RORγ inverse agonists/antagonists display tissue- and gene-context selectivity through distinct activities in altering chromatin accessibility and master regulator SREBP2 occupancy

Article

作者: Zou, Hongye ; Shi, Zhenrui ; Chen, Hong-Wu ; Yu, Ai-Ming ; Yang, Yatian ; Liu, Ruiwu ; Wu, Xuesong

The nuclear receptor RORγ is a major driver of autoimmune diseases and certain types of cancer due to its aberrant function in T helper 17 (Th17) cell differentiation and tumor cholesterol metabolism, respectively. Compound screening using the classic receptor-coactivator interaction perturbation scheme led to identification of many small-molecule modulators of RORγ(t). We report here that inverse agonists/antagonists of RORγ such as VTP-43742 derivative VTP-23 and TAK828F, which can potently inhibit the inflammatory gene program in Th17 cells, unexpectedly lack high potency in inhibiting the growth of TNBC tumor cells. In contrast, antagonists such as XY018 and GSK805 that strongly suppress tumor cell growth and survival display only modest activities in reducing Th17-related cytokine expression. Unexpectedly, we found that VTP-23 significantly induces the cholesterol biosynthesis program in TNBC cells. Our further mechanistic analyses revealed that VTP-23 enhances the local chromatin accessibility, H3K27ac mark and the cholesterol master regulator SREBP2 recruitment at the RORγ binding sites, whereas XY018 exerts the opposite activities. Yet, they display similar inhibitory effects on circadian rhythm program. Similar distinctions and contrasting activities between TAK828F and SR2211 in their effects on local chromatin structure at Il17 genes were also observed. Together, our study shows for the first-time that structurally distinct RORγ antagonists possess different or even contrasting activities in tissue/cell-specific manner. Our findings also highlight that the activities at natural chromatin are key determinants of RORγ modulators' tissue selectivity.

2022-02-01·Bioorganic chemistry2区 · 化学

Discovery of N-(2-benzyl-4-oxochroman-7-yl)-2-(5-(ethylsulfonyl) pyridin-2-yl) acetamide (b12) as a potent, selective, and orally available novel retinoic acid receptor-related orphan receptor γt inverse agonist

2区 · 化学

Article

作者: Su, Mei ; Liao, Zhi-Xin ; Sun, Bo ; Wang, Chun-Gu ; Assani, Israa ; Zhao, Shi-Feng ; Chen, Lei ; Jin, Qiu ; Li, Yan ; Wang, Jia-Wei ; Wang, Mu-Xuan ; Lv, Shen-Min

The nuclear receptor retinoic acid receptor-related orphan receptor γ (RORγ, NR1F3, or RORc) exists in two isoforms, with one isoform (RORγ or RORc1) widely expressed in a variety of tissues, and the expression of the second isoform (RORγt or RORc2) restricted to the thymus and cells of the immune system. RORγt is a key regulator of the development and functions of T-helper 17 (Th17) cells. Clinical proof-of-concept (PoC) with small molecule inverse agonists of RORγt has been achieved with VTP-43742 (Phase II) for the treatment of psoriasis, and pre-clinical PoC for this mechanism has also been established for the treatment of autoimmune diseases. A series of aryl sulfonyl derivatives as novel RORγt inverse agonists were designed and synthesized based on VTP-43742. We conducted structural modifications that improved the activity profile. In pharmacodynamic (PD) studies, oral administration of compound b12 showed robust and dose-dependent inhibition of IL-6 and IL-17A cytokine expression. The ability of compound b12 to reduce the levels of IL-6 and IL-17A in vivo after oral dosing in mice, and a corresponding reduction in skin inflammation further supports the potential of small molecule RORγt modulation as a therapeutic target for the treatment of inflammatory diseases.

2021-12-02·Expert opinion on drug discovery3区 · 医学

Retinoic acid-related orphan receptor gamma t (RORγt) inverse agonists/antagonists for the treatment of inflammatory diseases – where are we presently?

3区 · 医学

Review

作者: Gege, Christian

Introduction: The transcription factor retinoic acid-related orphan receptor gamma t (RORγt) has been identified as the master regulator of T_H17 cell differentiation and IL-17/22 production and is therefore an attractive target for the treatment of inflammatory diseases. Several orally or topically administered small molecule RORγt inverse agonists (RIAs) have progressed up to the end of clinical Phase 2.Areas covered: Based on publications and patent evaluations this review summarizes the evolution of the chemical matter for all 16 pharmaceutical companies, who develop(ed) a clinical-stage RIAs (until March 2021). Structure proposals for some clinical stage RIAs are presented and the outcome of the clinical trials is discussed.Expert opinion: So far, the clinical trials have been plagued with a high attrition rate. Main reasons were lack of efficacy (topical) or safety signals (oral) as well as, amongst other things, thymic lymphomas as seen with BMS-986251 in a preclinical study and liver enzyme elevations in humans with VTP-43742. Possibilities to mitigate these risks could be the use of RIAs with different chemical structures not interfering with thymocytes maturation and no livertox-inducing properties. With new frontrunners (e.g., ABBV-157 (cedirogant), BI 730357 or IMU-935) this is still an exciting time for this treatment approach.

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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

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
干眼综合征	临床2期	美国	Allergan Ltd. (Ireland)	2020-03-04
斑块状银屑病	临床2期	美国	Vitae Pharmaceuticals LLC	2017-11-15
银屑病关节炎	临床2期	美国	Vitae Pharmaceuticals LLC	2015-08-01

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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


NCT03339999 (CTgov)	临床2期	斑块状银屑病	24	Placebo (Placebo)	艱積鹽廠餘鹽繭獵壓鏇(觸糧範襯鏇鹽糧範艱鹹) = 衊觸齋壓廠簾壓淵觸壓鏇築襯糧廠衊鹹構獵繭 (憲齋鹽構廠襯選淵艱憲, 夢襯鹹衊網鑰餘醖築製 ~ 壓鬱鏇遞鹽衊網襯糧襯) 更多	-	2021-04-06
				AGN-242428 (AGN-242428 Higher Dose)	艱積鹽廠餘鹽繭獵壓鏇(觸糧範襯鏇鹽糧範艱鹹) = 鹽願選鹹製壓齋築構範鏇築襯糧廠衊鹹構獵繭 (憲齋鹽構廠襯選淵艱憲, 蓋選衊壓遞願願壓網餘 ~ 醖憲鏇壓積遞艱觸窪網) 更多
NCT02555709 (VTP-43742, AAI2016)	临床1/2期	IL-17A \| IL-23 receptor	40	VTP-43742	構醖築餘鹽鏇製廠憲窪(構獵衊鏇糧艱餘鹽製鑰) = No serious adverse events were reported, and all study subjects completed dosing 齋鏇積積衊製構選遞選 (觸鹽壓艱範衊選顧選壓 ) 更多	积极	2016-05-01
NCT03724292 (GlobeNewswire) 人工标引	临床1期	银屑病	40	VTP-43742	鹹觸願築繭憲鹹製築艱(醖鹽齋簾廠壓襯鹽製窪) = No serious adverse events were reported 壓遞蓋醖鹹糧膚糧獵築 (憲夢鏇願窪簾窪構夢廠 ) 更多	积极	2015-11-18
				Placebo