A Phase I, Two Parts Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of BAR502 in Healthy Subjects

First-in-human, single centre, two parts, dose-escalation, parallel-group, safety, tolerability, pharmacokinetic and pharmacodynamic Phase I study. Part A: randomised, double-blind, placebo-controlled, single ascending dose study.
Part B: open label, multiple ascending dose study.

Start Date04 Dec 2024

Sponsor / Collaborator

BAR Pharmaceuticals s.r.l.

NCT05203367

/ WithdrawnPhase 1

Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses of BAR 502 in Healthy Subjects

This is a prospective, single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 study to evaluate the safety and tolerability of single-ascending doses of BAR 502 in healthy male and female subjects.

Start Date25 Nov 2022

Sponsor / Collaborator

BAR Pharmaceuticals s.r.l.

100 Clinical Results associated with FXR x TGR5

100 Translational Medicine associated with FXR x TGR5

0 Patents (Medical) associated with FXR x TGR5

475

Literatures (Medical) associated with FXR x TGR5

01 Jan 2025·Archiv der Pharmazie

The discovery of a new nonbile acid modulator of Takeda G protein‐coupled receptor 5: An integrated computational approach

Article

Author: Štefela, Alžbeta ; Zitko, Jan ; Krutáková, Mária ; Pávek, Petr ; Salam, Rudy ; Bakker, Michael ; Duintjer Tebbens, Jurjen

AbstractThe Takeda G protein‐coupled receptor 5 (TGR5), also known as GPBAR1 (G protein‐coupled bile acid receptor), is a membrane‐type bile acid receptor that regulates blood glucose levels and energy expenditure. These essential functions make TGR5 a promising target for the treatment of type 2 diabetes and metabolic disorders. Currently, most research on developing TGR5 agonists focuses on modifying the structure of bile acids, which are the endogenous ligands of TGR5. However, TGR5 agonists with nonsteroidal structures have not been widely explored. This study aimed at discovering new TGR5 agonists using bile acid derivatives as a basis for a computational approach. We applied a combination of pharmacophore‐based, molecular docking, and molecular dynamic (MD) simulation to identify potential compounds as new TGR5 agonists. Through pharmacophore screening and molecular docking, we identified 41 candidate compounds. From these, five candidates were selected based on criteria including pharmacophore features, a docking score of less than 9.2 kcal/mol, and similarity in essential interaction patterns with a reference ligand. Biological assays of the five hits confirmed that Hit‐3 activates TGR5 similarly to the bile acid control. This was supported by MD simulation results, which indicated that a hydrogen bond interaction with Tyr240 is involved in TGR5 activation. Hit‐3 (CSC089939231) represents a new nonsteroidal lead that can be further optimized to design potent TGR5 agonists.

01 Jan 2025·Journal of Ethnopharmacology

Study on the mechanism on Yi-guan-jian decoction alleviating cognitive dysfunction in type 2 diabetes mellitus

Article

Author: Xie, Chunguang ; Yao, Nairong ; Zhang, Haiyan ; Wang, Fang ; Luo, Qiwei ; Yang, Qiyue ; He, Yanan ; Xia, Wenrui

ETHNOPHARMACOLOGICAL RELEVANCEYi-guan-jian decoction (YGJ) is a traditional Chinese medicine prescription commonly used for treating syndromes associated with Yin deficiency in the liver and kidney, as well as Qi-obstructed in liver.AIM OF THE STUDYYGJ has shown potential alleviating cognitive dysfunction in type 2 diabetes mellitus (T2DM). However, the precise mechanisms are not yet fully understood. This study aims to reveal the mechanism by which YGJ alleviates cognitive dysfunction in T2DM.MATERIALS AND METHODSVarious doses of YGJ were administered to T2DM rats with cognitive dysfunction for 8 weeks. The positive control group received a combination of metformin and memantine. Cognitive function was assessed in T2DM rats using the Morris water maze test during treatment. Changes in gut microbiota and bile acids in the intestine were evaluated, and their interactions analyzed. Additionally, this study also evaluated the expressions of inflammatory markers (IL-1β,TNF-α, IL-16, IL-18 and CRP protein), Tau protein, neurotransmitter (5-HT and GABA), and bile acid receptor (FXR, PXR, VDR, and TGR5).RESULTSYGJ significantly alleviated insulin resistance and hyperlipidemia, reduce the levels of inflammatory factors in serum and hippocampus, and decreased mortality in T2DM rats. The Morris water maze test indicated that YGJ reduced the escape latency and increased platform crossing frequency, thereby improving cognitive function in T2DM rats. Furthermore, YGJ regulated the abundance of microorganisms associated with bile acid metabolism, including Romboutsia, Bacteroides, Turicibacter, Blautia, and Ruminococcus, thus regulating bile acid metabolism in T2DM rats. Additionally, YGJ also regulated bile acid metabolism by regulating intestinal FXR, PXR, VDR and TRG5 receptors.CONCLUSIONYGJ can alleviate glucose homeostasis, insulin sensitivity, lipid metabolism, neuroinflammation, cognitive function, as well as remodel intestinal flora and BA composition in CDT2DM rats, which is a potential complementary and alternative therapy for the prevention and treatment of CDT2DM. These effects may be associated that YGJ regulates the structure of intestinal flora and BA metabolism, and inhibits intestinal BA receptors FXR, PXR, TGR5, and VDR.

01 Jan 2025·Molecular Metabolism

TGR5 receptors in SF1-expressing neurons of the ventromedial hypothalamus regulate glucose homeostasis

Article

Author: Leste-Lasserre, Thierry ; Fénelon, Valérie S ; Simon, Vincent ; Cota, Daniela ; Castellanos-Jankiewicz, Ashley ; Maître, Marlene ; Clark, Samantha ; Dupuy, Nathalie ; Zizzari, Philippe ; Yagoub, Selma ; Schoonjans, Kristina ; Gonzales, Delphine

OBJECTIVESteroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus play key roles in the regulation of food intake, body weight and glucose metabolism. The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) is expressed in the hypothalamus, where it determines some of the actions of bile acids on food intake and body weight through still poorly defined neuronal mechanisms. Here, we examined the role of TGR5 in SF1 neurons in the regulation of energy balance and glucose metabolism.METHODSWe used a genetic approach combined with metabolic phenotyping and molecular analyses to establish the effect of TGR5 deletion in SF1 neurons on meal pattern, body weight, body composition, energy expenditure and use of energy substrates as well as on possible changes in glucose handling and insulin sensitivity.RESULTSOur findings reveal that TGR5 in SF1 neurons does not play a major role in the regulation of food intake or body weight under standard chow, but it is involved in the adaptive feeding response to the acute exposure to cold or to a hypercaloric, high-fat diet, without changes in energy expenditure. Notably, TGR5 in SF1 neurons hinder glucose metabolism, since deletion of the receptor improves whole-body glucose uptake through heightened insulin signaling in the hypothalamus and in the brown adipose tissue.CONCLUSIONSTGR5 in SF1 neurons favours satiety by differently modifying the meal pattern in response to specific metabolic cues. These studies also reveal a novel key function for TGR5 in SF1 neurons in the regulation of whole-body insulin sensitivity, providing new insight into the role played by neuronal TGR5 in the regulation of metabolism.

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