Vercirnon Sodium(Vercirnon Sodium) - 药物靶点：CCR9_在研适应症：炎症性肠病_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Traficet-EN、Vercirnon、CCX-282

+ [8]

靶点

CCR9

作用方式

拮抗剂

作用机制

CCR9拮抗剂(C-C趋化因子受体9型拮抗剂)

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构

权益机构

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)无进展

特殊审评-

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结构/序列

分子式C22H21ClN2NaO4S

InChIKeyQFAUJPTYAGADMS-UHFFFAOYSA-N

CAS号886214-18-2

关联

13

项与 Vercirnon Sodium 相关的临床试验

NCT01827631

/ Completed临床1期

Single and Repeat Dose Pharmacokinetic Study of GSK1605786 in Healthy Chinese Subjects

This is an open-label, parallel group, single and repeat dose pharmacokinetic (PK) study in healthy male and female subjects. This study will confirm the PK and safety profile in Chinese subjects. GSK1605786 is currently in clinical development for the treatment of Crohn's disease. Subjects will receive one of two GSK1605786 doses (500 mg once daily or 500mg twice daily) within 30 minutes after a meal. The study will consist of single and repeat dose sessions, with pre-dose and serial PK samples taken up to 72-h post-dose.

开始日期2013-05-27

申办/合作机构

GSK Plc

EUCTR2011-002818-37-BE

/ Not yet recruiting临床2期

A phase II, 20-week, multi-centre, randomised, double-blind, placebo-controlled, parallel group proof of concept study to investigate the efficacy and safety of GSK1605786 for treatment of patients with active Ulcerative Colitis.

开始日期2012-02-15

申办/合作机构

GlaxoSmithKline Research & Development Ltd.

NCT01536418

/ Terminated临床3期

A Randomised, Double-blind, Active Treatment Study to Induce Clinical Response and/or Remission With GSK1605786A in Subjects With Moderately-to-Severely Active Crohn's Disease

This is a multi-centre, randomised, double-blind, active treatment, parallel group induction study in subjects with moderately-to-severely active Crohn's disease. Subjects will receive one of two doses (500 milligrams once daily, 500 milligrams twice daily) of GSK1605786A for 12 weeks. The primary objective of the study is to induce clinical response (Crohn's Disease Activity Index [CDAI] decrease from baseline of at least 100 points) and/or remission (CDAI score less than 150) with GSK1605786A at Week 12 in subjects with active Crohn's disease to qualify subjects for enrolment into a 52 week maintenance study (CCX114157). Secondary objectives will include assessment of the safety and evaluation of the efficacy in induction of clinical response or remission. Safety will be assessed by recording of adverse events and assessment of changes in clinical laboratory parameters, vital signs and electrocardiogram. Population pharmacokinetics will evaluate the two doses of GSK1605786A. Health outcomes assessments will include changes in Inflammatory Bowel Disease Questionnaire, SF-36, EQ-5D, and Work Productivity and Activity Impairment-Crohn's Disease.

开始日期2011-11-11

申办/合作机构

GSK Plc

100 项与 Vercirnon Sodium 相关的临床结果

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100 项与 Vercirnon Sodium 相关的转化医学

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100 项与 Vercirnon Sodium 相关的专利（医药）

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27

项与 Vercirnon Sodium 相关的文献（医药）

2024-10-16·ChemMedChem

Development of a NanoBRET Assay Platform to Detect Intracellular Ligands for the Chemokine Receptors CCR6 and CXCR1

Article

作者: Schiedel, Matthias ; Chevigné, Andy ; Toy, Lara ; Kostenis, Evi ; Moumbock, Aurélien F. A. ; Hansen, Finn K. ; Alonso Bartolomé, Ana ; Szpakowska, Martyna ; Günther, Stefan ; Huber, Max E. ; Wurnig, Silas L.

Abstract:

A conserved intracellular allosteric binding site (IABS) was recently identified at several G protein‐coupled receptors (GPCRs). This target site allows the binding of allosteric modulators and enables a new mode of GPCR inhibition. Herein, we report the development of a NanoBRET‐based assay platform based on the fluorescent ligand LT221 (5), to detect intracellular binding to CCR6 and CXCR1, two chemokine receptors that have been pursued as promising drug targets in inflammation and immuno‐oncology. Our assay platform enables cell‐free as well as cellular NanoBRET‐based binding studies in a nonisotopic and straightforward manner. By combining this screening platform with a previously reported CXCR2 assay, we investigated CXCR1/CXCR2/CCR6 selectivity profiles for both known and novel squaramide analogues derived from navarixin, a known intracellular CXCR1/CXCR2 antagonist and phase II clinical candidate for the treatment of pulmonary diseases. By means of these studies we identified compound 10, a previously reported tert‐butyl analogue of navarixin, as a low nanomolar intracellular CCR6 antagonist. Further, our assay platform clearly indicated intracellular binding of the CCR6 antagonist PF‐07054894, currently evaluated in phase I clinical trials for the treatment of ulcerative colitis, thereby providing profound evidence for the existence and the pharmacological relevance of a druggable IABS at CCR6.

2022-03-14·Angewandte Chemie (International ed. in English)

A Chemical Biology Toolbox Targeting the Intracellular Binding Site of CCR9: Fluorescent Ligands, New Drug Leads and PROTACs

Article

作者: Toy, Lara ; Schiedel, Matthias ; Merten, Nicole ; Kostenis, Evi ; Weikert, Dorothee ; Budzinski, Julian ; Huber, Max E. ; Wiefhoff, Martin F. J. ; Vogt, Hannah ; Schmidt, Maximilian F.

Abstract:

A conserved intracellular allosteric binding site (IABS) has recently been identified at several G protein‐coupled receptors (GPCRs). Starting from vercirnon, an intracellular C−C chemokine receptor type 9 (CCR9) antagonist and previous phase III clinical candidate for the treatment of Crohn's disease, we developed a chemical biology toolbox targeting the IABS of CCR9. We first synthesized a fluorescent ligand enabling equilibrium and kinetic binding studies via NanoBRET as well as fluorescence microscopy. Applying this molecular tool in a membrane‐based setup and in living cells, we discovered a 4‐aminopyrimidine analogue as a new intracellular CCR9 antagonist with improved affinity. To chemically induce CCR9 degradation, we then developed the first PROTAC targeting the IABS of GPCRs. In a proof‐of‐principle study, we succeeded in showing that our CCR9‐PROTAC is able to reduce CCR9 levels, thereby offering an unprecedented approach to modulate GPCR activity.

2020-12-01·Metabolism: clinical and experimental1区 · 医学

The role of the CCL25-CCR9 axis in beta-cell function: potential for therapeutic intervention in type 2 diabetes

1区 · 医学

Article

作者: Huang, Guo Cai ; Lee, Vivian ; Persaud, Shanta J ; Atanes, Patricio

BACKGROUND AND PURPOSE:

Chemokines are known to play essential roles mediating immunity and inflammation in many physiological and pathophysiological processes, with reports linking their action to the development of obesity, insulin resistance and type 2 diabetes (T2D). Given our findings of highly upregulated mRNA expression of the chemokine receptor CCR9 in islets from obese human donors, we have determined the effects of CCR9 activation by CCL25 on islet function and viability.

BASIC PROCEDURES:

RT-qPCR was used to measure expression of 384 GPCR mRNAs in human islets from organ donors with normal and elevated BMI. mRNA encoding CCR9, a receptor that was highly upregulated in islets from obese donors, was also quantified in islets from lean and high-fat diet (HFD) mice. The effects of CCR9 activation by exogenous CCL25 in human and mouse islets and its inhibition by the CCR9 antagonist vercirnon on insulin secretion, apoptosis and cAMP accumulation were examined using standard techniques.

MAIN FINDINGS:

The qPCR analysis showed altered expression of several GPCRs in islets isolated from lean and obese donors. CCR9 displayed over 90-fold upregulation in islets from obese individuals, and it was also significantly upregulated in islets from obese mice. In isolated human and mouse islets exogenous CCL25 inhibited glucose-induced insulin secretion in a concentration-dependent manner, enhanced cytokine-induced apoptosis and significantly reduced forskolin-induced elevation in cAMP levels. These detrimental effects of CCL25 in islets were blocked by vercirnon, which had no effect on its own.

PRINCIPAL CONCLUSIONS:

We have shown that CCL25 acts via the Gαi-coupled receptor CCR9 to impair beta-cell function by inhibiting insulin secretion and promoting cytokine-induced apoptosis. Upregulation of CCR9 in islets in obesity, possibly secondary to accumulation of passenger immune cells, may predispose to metabolic dysfunction and our data suggest that CCL25 downregulation or CCR9 inhibition could be explored to treat T2D.

100 项与 Vercirnon Sodium 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15250

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
克罗恩病	临床3期	美国	GSK Plc	2010-12-20
克罗恩病	临床3期	日本	GSK Plc	2010-12-20
克罗恩病	临床3期	澳大利亚	GSK Plc	2010-12-20
克罗恩病	临床3期	奥地利	GSK Plc	2010-12-20
克罗恩病	临床3期	比利时	GSK Plc	2010-12-20
克罗恩病	临床3期	加拿大	GSK Plc	2010-12-20
克罗恩病	临床3期	捷克	GSK Plc	2010-12-20
克罗恩病	临床3期	丹麦	GSK Plc	2010-12-20
克罗恩病	临床3期	法国	GSK Plc	2010-12-20
克罗恩病	临床3期	德国	GSK Plc	2010-12-20

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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


NCT01277666 (SHIELD-1, CTgov)	临床3期	克罗恩病	608	Placebo	膚壓憲艱顧遞淵觸醖鬱 = 鏇襯衊窪餘醖襯顧範鬱襯襯願糧積遞顧齋艱窪 (觸醖鑰淵獵淵構鏇艱簾, 願憲窪觸鏇築網鹹範淵 ~ 廠製獵衊廠淵範蓋齋製) 更多	-	2017-09-19
NCT01318993 (SHIELD-3, CTgov)	临床3期	克罗恩病	399	GSK1605786A	衊壓窪範夢餘構艱範築(艱獵網獵齋蓋糧選憲襯) = 鏇襯襯網窪簾網構鹹醖憲觸網醖憲夢築簾積簾 (鏇網衊範鏇顧齋醖齋衊, 簾糧糧醖鹽構遞窪範築 ~ 繭鹹選鬱鹹鏇網糧觸衊) 更多	-	2017-09-14
NCT01316939 (SHIELD-2, CTgov)	临床3期	克罗恩病	229	Placebo	鏇鏇繭範範鏇積繭獵衊 = 齋鹹獵願醖壓壓蓋蓋鬱製襯鹹鏇繭築選築鬱膚 (醖願顧製衊觸壓積醖鏇, 繭遞築夢齋襯遞鹹齋獵 ~ 選鏇廠醖艱積壓簾範繭) 更多	-	2017-09-07
NCT01536418 (SHIELD-4, CTgov)	临床3期	克罗恩病	255	GSK1605786A (GSK1605786A 500 mg, Once Daily)	憲鏇觸衊繭夢壓範淵鏇 = 願範衊選廠築艱壓鏇齋顧淵製醖觸壓範壓願構 (網築鹽獵製選艱蓋構壓, 糧範艱鹽繭獵艱窪觸遞 ~ 膚築構選淵觸範糧簾鹹) 更多	-	2017-08-17
				GSK1605786A (GSK1605786A 500 mg,Twice Daily)	憲鏇觸衊繭夢壓範淵鏇 = 憲築淵構蓋鏇願遞遞餘顧淵製醖觸壓範壓願構 (網築鹽獵製選艱蓋構壓, 範顧顧膚憲製蓋範淵壓 ~ 憲鑰醖鹽鬱醖憲廠廠糧) 更多
PROTECT-1 \| SHIELD-1 (UEGW2014)	临床2/3期	克罗恩病 CRP \| fecal calprotectin	-	Vercirnon 500 mg QD	遞鹹艱鏇鹽窪膚蓋遞淵(憲鏇遞繭繭襯廠鑰窪選) = more GI adverse events were found in SHIELD-1, in particular at the highest dose, 500 mg BID, which was not tested in PROTECT-1 範鹽鑰齋鏇夢獵築醖廠 (簾壓築憲簾製製鬱鬱鏇 )	不佳	2014-10-01
				Vercirnon 500 mg BID
NCT00306215 (Pubmed \| PLoS One)	临床2期	克罗恩病	436	Placebo	餘築壓顧衊醖齋膚鹹鑰(顧窪餘網鏇鹽齋襯壓鏇) = 蓋簾壓網顧鹽鏇觸願淵醖顧鬱窪積壓願夢襯鹹 (簾遞齋顧窪衊遞鬱鬱顧 ) 更多	-	2013-01-01
				CCX282-B 250 mg once daily	餘築壓顧衊醖齋膚鹹鑰(顧窪餘網鏇鹽齋襯壓鏇) = 鏇鑰鑰壓壓廠鏇築蓋糧醖顧鬱窪積壓願夢襯鹹 (簾遞齋顧窪衊遞鬱鬱顧 ) 更多