A Double-Blind, Double-Dummy, Placebo- and Active-Controlled Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Inflammatory Effects of GSK1399686 in Patients With Mild to Moderately Active Ulcerative Colitis

This study is the first-time-in-patient trial of GSK1399686, a novel locally-acting anti-inflammatory compound, aimed at obtaining initial information on the tolerability, safety, pharmacokinetics (including concentrations in colon mucosa) and anti-inflammatory activity of GSK1399686 upon oral dosing in patients with active ulcerative colitis.
The study is designed as a randomized, double-blind, double-dummy, placebo-controlled, sequential dose escalating trial, with an active control (ASACOL) group as internal control. Up to three cohorts (Cohorts 1-3), each consisting of approximately 20 patients with mild-moderately active ulcerative colitis not limited to the rectum, will be included, one for each dose level of GSK1399686 to be tested. Within a cohort, patients will be randomized in a 3:1:1 ratio to receive GSK1399686 (once daily over 4 weeks, followed by 2 weeks dosing with placebo), placebo, or ASACOL (t.i.d. for 6 weeks), respectively.
An interim analysis of fecal markers and disease activity data will be performed by the end of Cohort 3. Based upon results, the study may be stopped or continued by recruiting either Cohort 4 (if data on an additional dose level would be warranted to establish or clarify a dose-response relationship) or, in the case of a robust efficacy signal at any dose level previously studied, Cohort 5 (to expand the sample size for given dose level in order to evaluate the efficacy of GSK1399686). The number of patients and randomization allocation ratio may be altered in Cohort 5 and it may not include an active control arm. If Cohort 4 is initiated upon interim analysis, then a second interim analysis may be performed at the end of Cohort 4, to assess whether progression into Cohort 5 (as defined above) would be justifiable.

Start Date15 Sep 2009

Sponsor / Collaborator

GSK Plc

EUCTR2009-011608-51-BE

/ Not yet recruitingPhase 2

Start Date03 Aug 2009

Sponsor / Collaborator

GlaxoSmithKline Research & Development Ltd.

NCT00721812

/ CompletedPhase 1

A First Time In Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of GSK1399686 After Single and Repeated Oral Dosing in Healthy Volunteers Using a Dose-Escalating, Randomized, Placebo-Controlled Study Design

A First-Time-in-Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of GSK1399686 After Single and Repeated Oral Dosing in Healthy Volunteers

Start Date25 Sep 2008

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with Draflazine

100 Translational Medicine associated with Draflazine

100 Patents (Medical) associated with Draflazine

Literatures (Medical) associated with Draflazine

01 Oct 2024·DRUG METABOLISM AND DISPOSITION

Development of a Novel HEK293 Cell Model Lacking SLC29A1 to Study the Pharmacology of Endogenous SLC29A2-Encoded Equilibrative Nucleoside Transporter Subtype 2

Article

Author: Cromwell, Christopher ; Shahid, Nayiar ; Hammond, James R ; Hubbard, Basil P

Equilibrative nucleoside transporters (ENTs) mediate the transmembrane flux of endogenous nucleosides and nucleoside analogs used clinically. The predominant subtype, ENT1, has been well characterized. However, the other subtype, ENT2, has been less well characterized in its native milieu due to its relatively low expression and the confounding influence of coexpressed ENT1. We created a cell model where ENT1 was removed from human embryonic kidney (HEK293) cells using CRISPR/cas9 [ENT1 knockout (KO) cells]; this cell line has ENT2 as the only functional purine transporter. Transporter function was assessed through measurement of [³H]2-chloroadenosine uptake. ENT1 protein was quantified based on the binding of [³H]nitrobenzylthioinosine, and ENT1/ENT2 protein was detected by immunoblotting. Changes in expression of relevant transporters and enzymes involved in purine metabolism were examined by quantitative polymerase chain reaction. Wild-type HEK293 cells and ENT1KO cells had a similar expression of SLC29A2/ENT2 transcript/protein and ENT2-mediated [³H]2-chloroadenosine transport activity (V_max values of 1.02 ± 0.06 and 1.50 ± 0.22 pmol/μl/s, respectively). Of the endogenous nucleosides/nucleobases tested, adenosine had the highest affinity (K_i) for ENT2 (2.6 μM), while hypoxanthine was the only nucleobase with a submillimolar affinity (320 μM). A range of nucleoside/nucleobase analogs were also tested for their affinity for ENT2 in this model, with affinities (K_i) ranging from 8.6 μM for ticagrelor to 2,300 μM for 6-mercaptopurine. Our data suggest that the removal of endogenous ENT1 from these cells does not change the expression or function of ENT2. This cell line should prove useful for the analysis of novel drugs acting via ENT2 and to study ENT2 regulation. SIGNIFICANCE STATEMENT: We have created a cell line whereby endogenous ENT2 can be studied in detail in the absence of the confounding influence of ENT1. Loss of ENT1 has no impact on the expression and function of ENT2. This novel cell line will provide an ideal model for studying drug interactions with ENT2 as well as the cellular regulation of ENT2 expression and function.

01 Feb 2020·BIOCHEMICAL PHARMACOLOGY

Affinity, binding kinetics and functional characterization of draflazine analogues for human equilibrative nucleoside transporter 1 (SLC29A1)

Article

Author: Vlachodimou, Anna ; IJzerman, Adriaan P ; Konstantinopoulou, Konstantina ; Heitman, Laura H

In the last decade it has been recapitulated that receptor-ligand binding kinetics is a relevant additional parameter in drug discovery to improve in vivo drug efficacy and safety. The equilibrative nucleoside transporter-1 (ENT1, SLC29A1) is an important drug target, as transporter inhibition is a potential treatment of ischemic heart disease, stroke, and cancer. Currently, two non-selective ENT1 inhibitors (dilazep and dipyridamole) are on the market as vasodilators. However, their binding kinetics are unknown; moreover, novel, more effective and selective inhibitors are still needed. Hence, this study focused on the incorporation of binding kinetics for finding new and improved ENT1 inhibitors. We developed a radioligand competition association assay to determine the binding kinetics of ENT1 inhibitors with four chemical scaffolds (including dilazep and dipyridamole). The kinetic parameters were compared to the affinities obtained from a radioligand displacement assay. Three of the scaffolds presented high affinities with relatively fast dissociation kinetics, yielding short to moderate residence times (RTs) at the protein (1-44 min). While compounds from the fourth scaffold, i.e. draflazine analogues, also had high affinity, they displayed significantly longer RTs, with one analogue (4) having a RT of over 10 h. Finally, a label-free assay was used to evaluate the impact of divergent ENT1 inhibitor binding kinetics in a functional assay. It was shown that the potency of compound 4 increased with longer incubation times, which was not observed for draflazine, supporting the importance of long RT for increased target-occupancy and effect. In conclusion, our research shows that high affinity ENT1 inhibitors show a large variation in residence times at this transport protein. As a consequence, incorporation of binding kinetic parameters adds to the design criteria and may thus result in a different lead compound selection. Taken together, this kinetic approach could inspire future drug discovery in the field of ENT1 and membrane transport proteins in general.

01 Feb 2017·Toxicology and applied pharmacologyQ3 · MEDICINE

A semi-quantitative translational pharmacology analysis to understand the relationship between in vitro ENT1 inhibition and the clinical incidence of dyspnoea and bronchospasm

Q3 · MEDICINE

Review

Author: Ian Storer, R ; Rosenbrier Ribeiro, Lyn

Adenosine contributes to the pathophysiology of respiratory disease, and adenosine challenge leads to bronchospasm and dyspnoea in patients. The equilibrative nucleoside transporter 1 (ENT1) terminates the action of adenosine by removal from the extracellular environment. Therefore, it is proposed that inhibition of ENT1 in respiratory disease patients leads to increased adenosine concentrations, triggering bronchospasm and dyspnoea. This study aims to assess the translation of in vitro ENT1 inhibition to the clinical incidence of bronchospasm and dyspnoea in respiratory disease, cardiovascular disease and healthy volunteer populations. Four marketed drugs with ENT1 activity were assessed; dipyridamole, ticagrelor, draflazine, cilostazol. For each patient population, the relationship between in vitro ENT1 [³H]-NBTI binding affinity (K_i) and [³H]-adenosine uptake (IC₅₀) to the incidence of: (1) bronchospasm/severe dyspnoea; (2) tolerated dyspnoea and; (3) no adverse effects, was evaluated. A high degree of ENT1 inhibition (≥13.3x K_i, ≥4x IC₅₀) associated with increased incidence of bronchospasm/severe dyspnoea for patients with respiratory disease only, whereas a lower degree of ENT1 inhibition (≥0.1x K_i, ≥0.05x IC₅₀) associated with a tolerable level of dyspnoea in both respiratory and cardiovascular disease patients. ENT1 inhibition had no effect in healthy volunteers. Furthermore, physicochemical properties correlative with ENT1 binding were assessed using a set of 1625 diverse molecules. Binding to ENT1 was relatively promiscuous (22% compounds K_i<1μM) especially for neutral or basic molecules, and greater incidence tracked with higher lipophilicity (clogP >5). This study rationalises inclusion of an assessment of ENT1 activity during early safety profiling for programs targeting respiratory disorders.

100 Deals associated with Draflazine

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis, Ulcerative	Phase 2	Belgium	GSK Plc	15 Sep 2009
Colitis, Ulcerative	Phase 2	Canada	GSK Plc	15 Sep 2009
Colitis, Ulcerative	Phase 2	Germany	GSK Plc	15 Sep 2009
Colitis, Ulcerative	Phase 2	Norway	GSK Plc	15 Sep 2009
Colitis, Ulcerative	Phase 2	Sweden	GSK Plc	15 Sep 2009
Inflammatory Bowel Diseases	Phase 1	United Kingdom	GSK Plc	25 Sep 2008

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01036022 (CTgov)	Phase 2	Colitis, Ulcerative	120	placebo+asacol+GSK1399686 (Placebo)	bslzqknrqb = syymqmrqum eipkllajls (vbaiwapaoi, rxdneckxwt - mabuqypmfq) View more	-	26 Jun 2017
				GSK1399686 (GSK1399686 10 mg)	bslzqknrqb = kkuofvomng eipkllajls (vbaiwapaoi, ypltkxqkba - yccckstymz) View more

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