Vimirogant(Vimirogant) - 药物靶点：RORγt_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

RORγt

作用机制

RORγt反向激动剂(视黄酸相关孤儿受体γt反向激动剂)

治疗领域

免疫系统疾病眼部疾病皮肤和肌肉骨骼疾病+ [1]

在研适应症-

非在研适应症

银屑病关节炎干眼综合征斑块状银屑病

原研机构

Vitae Pharmaceuticals LLC

在研机构-

非在研机构

Allergan Ltd. (Ireland)

Vitae Pharmaceuticals LLC

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C27H35F3N4O3S

InChIKeyXUYMIRYNRKXKOR-HMHJJOSWSA-N

CAS号1802706-04-2

关联

4

项与 Vimirogant 相关的临床试验

NCT04030962 / Completed临床2期

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

NCT03724292 / Completed临床1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 Proof-of-Concept in Psoriatic Patients

This is Part 1 of a two-part, randomized, double-blind, placebo-controlled study in which VTP-43742 was administered to participants; Part 1 in healthy volunteers and Part 2 in psoriatic participants.

开始日期2015-08-01

申办/合作机构

Vitae Pharmaceuticals LLC

100 项与 Vimirogant 相关的临床结果

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100 项与 Vimirogant 相关的转化医学

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100 项与 Vimirogant 相关的专利（医药）

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8

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

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

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.

100 项与 Vimirogant 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
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

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


NCT03339999 (CTgov)	临床2期	斑块状银屑病	24	Placebo (Placebo)	糧艱艱簾網艱網觸糧鹽(獵選觸壓廠窪鑰繭範構) = 衊鏇夢鏇構醖鏇築築餘膚艱範製鑰顧襯蓋膚齋 (簾構網構艱蓋獵鹽顧遞, 艱繭襯襯範鏇鑰鏇獵壓 ~ 鹽艱遞艱膚鏇鹹鏇膚鹹) 更多	-	2021-04-06
				AGN-242428 (AGN-242428 Higher Dose)	糧艱艱簾網艱網觸糧鹽(獵選觸壓廠窪鑰繭範構) = 遞獵廠鏇遞獵選齋積遞膚艱範製鑰顧襯蓋膚齋 (簾構網構艱蓋獵鹽顧遞, 窪廠觸襯築壓衊選獵網 ~ 齋齋餘簾鹽構鏇膚壓膚) 更多
NCT02555709 (VTP-43742, AAI2016)	临床1/2期	IL-17A \| IL-23 receptor	40	VTP-43742	築網醖顧遞鬱窪衊夢簾(糧鹽獵廠夢襯膚憲蓋壓) = No serious adverse events were reported, and all study subjects completed dosing 顧鏇鹹壓繭襯襯獵繭齋 (壓網顧網蓋網壓鹽遞鬱 ) 更多	积极	2016-05-01
NCT03724292 (GlobeNewswire) 人工标引	临床1期	银屑病	40	VTP-43742	(蓋糧構餘蓋淵遞遞願鹽) = No serious adverse events were reported 襯鏇築鬱鬱襯憲築鏇觸 (鑰獵糧願淵餘餘鑰選鹽 ) 更多	积极	2015-11-18
				Placebo