Delving into the Latest Updates on Vercirnon Sodium with Synapse

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.

Start Date27 May 2013

Sponsor / Collaborator

GSK Plc

EUCTR2011-002818-37-BE

/ Not yet recruitingPhase 2

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.

Start Date15 Feb 2012

Sponsor / Collaborator

GlaxoSmithKline Research & Development Ltd.

NCT01536418

/ TerminatedPhase 3

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.

Start Date11 Nov 2011

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with Vercirnon Sodium

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100 Translational Medicine associated with Vercirnon Sodium

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100 Patents (Medical) associated with Vercirnon Sodium

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31

Literatures (Medical) associated with Vercirnon Sodium

16 Oct 2024·ChemMedChem

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

Article

Author: Schiedel, Matthias ; Chevigné, Andy ; Kostenis, Evi ; Toy, Lara ; Moumbock, Aurélien F. A. ; Hansen, Finn K. ; Günther, Stefan ; Szpakowska, Martyna ; Alonso Bartolomé, Ana ; 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.

14 Mar 2022·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

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

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.

01 Dec 2020·Metabolism: clinical and experimentalQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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 Deals associated with Vercirnon Sodium

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Crohn Disease	Phase 3	United States	GSK Plc	20 Dec 2010
Crohn Disease	Phase 3	Japan	GSK Plc	20 Dec 2010
Crohn Disease	Phase 3	Australia	GSK Plc	20 Dec 2010
Crohn Disease	Phase 3	Austria	GSK Plc	20 Dec 2010
Crohn Disease	Phase 3	Belgium	GSK Plc	20 Dec 2010
Crohn Disease	Phase 3	Canada	GSK Plc	20 Dec 2010
Crohn Disease	Phase 3	Czechia	GSK Plc	20 Dec 2010
Crohn Disease	Phase 3	Denmark	GSK Plc	20 Dec 2010
Crohn Disease	Phase 3	France	GSK Plc	20 Dec 2010
Crohn Disease	Phase 3	Germany	GSK Plc	20 Dec 2010

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Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01277666 (SHIELD-1, CTgov)	Phase 3	Crohn Disease	608	Placebo	zmrdytjzev = uityjcijte uahmprdnrb (mrytrznpyd, ecthmmuynu - rsuqlujmvn) View more	-	19 Sep 2017
NCT01318993 (SHIELD-3, CTgov)	Phase 3	Crohn Disease	399	GSK1605786A	imwlsstwio(icchivznxg) = krsozpdvhf plzqgrkare (rpwwpmyuff, rrrlglymts - sgigqvcqll) View more	-	14 Sep 2017
NCT01316939 (SHIELD-2, CTgov)	Phase 3	Crohn Disease	229	Placebo	zdgtjjynci = chbpzjchlh zppnzzowcj (ukydqsyntr, rgvxyxwydx - uyuwtpiowd) View more	-	07 Sep 2017
NCT01536418 (SHIELD-4, CTgov)	Phase 3	Crohn Disease	255	GSK1605786A (GSK1605786A 500 mg, Once Daily)	ythwraamkq = mwunemzxnt zplxkqbxgt (iyrfdqejrk, vmrshoxuxy - zavbbkjanp) View more	-	17 Aug 2017
				GSK1605786A (GSK1605786A 500 mg,Twice Daily)	ythwraamkq = pupkvbvgrf zplxkqbxgt (iyrfdqejrk, fkwwnsabxm - swoehvcrha) View more
PROTECT-1 \| SHIELD-1 (UEGW2014)	Phase 2/3	Crohn Disease CRP \| fecal calprotectin	-	Vercirnon 500 mg QD	yfckcuouez(knjxhzufsa) = 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 tlaewerrzm (pvxstziigp )	Negative	01 Oct 2014
				Vercirnon 500 mg BID
NCT00306215 (Pubmed)	Phase 2	Crohn Disease	436	Placebo	fikpdulmfr(wtsyjlygmt) = hdxrsprack mhfbbdlvyz (tdvjapdroa ) View more	-	01 Jan 2013
				CCX282-B 250 mg once daily	fikpdulmfr(wtsyjlygmt) = bsoxymkyno mhfbbdlvyz (tdvjapdroa ) View more