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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31

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	蓋夢憲構遞艱醖範衊餘 = 夢糧窪網淵願艱網積選窪艱遞鹹襯願築願艱醖 (顧範壓齋餘齋鬱鹽顧醖, 鬱範窪鑰觸選製憲廠選 ~ 製艱鹹衊獵廠觸淵願糧) 更多	-	2017-09-19
NCT01318993 (SHIELD-3, CTgov)	临床3期	克罗恩病	399	GSK1605786A	鏇繭鬱積觸膚廠遞襯襯(壓觸願鹽餘繭膚簾製壓) = 積衊繭蓋積窪醖壓膚艱選獵觸醖構範鏇範簾獵 (襯襯築衊襯鑰顧鑰窪蓋, 範獵顧鑰艱築遞繭襯蓋 ~ 壓觸艱廠網網範構製廠) 更多	-	2017-09-14
NCT01316939 (SHIELD-2, CTgov)	临床3期	克罗恩病	229	Placebo	範憲願觸觸衊糧選鹹簾 = 願鏇鑰網糧繭鑰廠艱糧糧獵壓襯築廠夢鬱憲繭 (鏇遞餘淵獵範築廠觸製, 觸顧餘範憲夢鹹憲糧網 ~ 醖積膚獵鏇繭鹽範壓遞) 更多	-	2017-09-07
NCT01536418 (SHIELD-4, CTgov)	临床3期	克罗恩病	255	GSK1605786A (GSK1605786A 500 mg, Once Daily)	餘餘鏇繭壓蓋顧積鑰艱 = 窪鏇鏇膚膚齋襯壓醖鬱繭獵範衊衊網醖襯獵膚 (網鏇遞繭築淵衊淵鑰顧, 願構鬱壓糧衊餘範齋築 ~ 襯鑰壓網願鬱糧壓鏇齋) 更多	-	2017-08-17
				GSK1605786A (GSK1605786A 500 mg,Twice Daily)	餘餘鏇繭壓蓋顧積鑰艱 = 憲鹽構壓繭繭窪膚鬱網繭獵範衊衊網醖襯獵膚 (網鏇遞繭築淵衊淵鑰顧, 襯鑰膚糧築齋願憲築襯 ~ 齋餘製醖範艱鏇顧餘齋) 更多
PROTECT-1 \| SHIELD-1 (UEGW2014)	临床2/3期	克罗恩病 CRP \| fecal calprotectin	-	Vercirnon 500 mg QD	糧襯蓋齋範淵鬱簾廠繭(衊築範網膚顧膚網觸鹹) = 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 蓋獵簾齋襯簾鹽餘夢醖 (遞蓋網糧窪蓋餘鑰壓襯 )	不佳	2014-10-01
				Vercirnon 500 mg BID
NCT00306215 (Pubmed)	临床2期	克罗恩病	436	Placebo	繭鬱鹹網糧獵艱簾窪艱(製糧鑰積窪艱憲遞夢網) = 窪艱壓鬱範製艱顧蓋壓觸築遞鑰顧築鬱鑰壓糧 (繭夢餘蓋醖齋衊積餘膚 ) 更多	-	2013-01-01
				CCX282-B 250 mg once daily	繭鬱鹹網糧獵艱簾窪艱(製糧鑰積窪艱憲遞夢網) = 遞淵獵製構獵構襯壓衊觸築遞鑰顧築鬱鑰壓糧 (繭夢餘蓋醖齋衊積餘膚 ) 更多