Last update 21 Nov 2024

FXR and TGR5 ligands 30(Università degli Studi di Napoli Federico II)

Last update 21 Nov 2024

Overview

R&D Status

Clinical Result

Translational Medicine

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol, NorECDCOH

Target

FXR x TGR5

Mechanism

FXR modulators(Bile acid receptor FXR modulators), TGR5 modulators(G-protein coupled bile acid receptor 1 modulators)

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

Università degli Studi di Napoli Federico II

Active Organization

Università degli Studi di Napoli Federico II

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC25H44O3

InChIKeyHYCMOIGNYNCMRH-APIYUPOTSA-N

CAS Registry1612191-86-2

100 Clinical Results associated with FXR and TGR5 ligands 30(Università degli Studi di Napoli Federico II)

100 Translational Medicine associated with FXR and TGR5 ligands 30(Università degli Studi di Napoli Federico II)

100 Patents (Medical) associated with FXR and TGR5 ligands 30(Università degli Studi di Napoli Federico II)

Literatures (Medical) associated with FXR and TGR5 ligands 30(Università degli Studi di Napoli Federico II)

01 Oct 2024·Inflammation Research

DGA ameliorates severe acute pancreatitis through modulating macrophage pyroptosis

Article

Author: Yue, Xiyue ; Wang, Ruina ; Wang, Yanping ; Li, Yunsen ; Xie, Qing ; Tan, Lulu ; Lai, Lunmeng

Severe acute pancreatitis (SAP) is an inflammatory disease with varying severity, ranging from mild local inflammation to severe systemic disease, with a high incidence rate and mortality. Current drug treatments are not ideal. Therefore, safer and more effective therapeutic drugs are urgently needed. 7α,14β-dihydroxy-ent-kaur-17-dimethylamino-3,15-dione DGA, a diterpenoid compound derivatized from glaucocalyxin A, exhibits anti-inflammatory activity. In this study, we demonstrated the therapeutic potential of DGA against SAP and elucidated the underlying mechanisms. Treatment with DGA markedly (1) inhibited death of RAW264.7 and J774a.1 cells induced by Nigericin and lipopolysaccharide, (2) alleviated edema, acinar cell vacuolation, necrosis, and inflammatory cell infiltration of pancreatic tissue in mice, and (3) inhibited the activity of serum lipase and the secretion of inflammatory factor IL-1β. DGA significantly reduced the protein expression of IL-1β and NLRP3 and inhibited the phosphorylation of NF-κB. However, DGA exhibited no inhibitory effect on the expression of caspase-1, gasdermin D (GSDMD), NF-κB, TNF-α, or apoptosis-associated speck-like protein (ASC) and on the cleavage of caspase-1 or GSDMD. Molecular docking simulation confirmed that DGA can bind to TLR4 and IL-1 receptor. In conclusion, DGA may effectively alleviate the symptoms of SAP in mice and macrophages by inhibiting the binding of TLR4 and IL-1 receptor to their ligands; therefore, DGA is a promising drug candidate for the treatment of patients with SAP.

01 Jul 2021·HepatologyQ1 · MEDICINE

Dual Agonist of Farnesoid X Receptor and Takeda G Protein‐Coupled Receptor 5 Inhibits Hepatitis B Virus Infection In Vitro and In Vivo

Q1 · MEDICINE

Article

Author: Watashi, Koichi ; Sakamoto, Kazumasa ; Inoue, Rieko ; Takeuchi, Junko S ; Yamauchi, Taeko ; Umezawa, Kazuo ; Iguchi, Yusuke ; Une, Mizuho ; Ito, Kiyoaki ; Yamashita, Yukiko ; Okumura, Akinori ; Wakita, Takaji ; Yoneda, Masashi

Background and AimsChronic HBV infection is a major health problem worldwide. Currently, the first‐line treatment for HBV is nucleos(t)ide analogs or interferons; however, efficient therapeutic approaches that enable cure are lacking. Therefore, anti‐HBV agents with mechanisms distinct from those of current drugs are needed. Sodium taurocholate cotransporting polypeptide (NTCP) was previously identified as an HBV receptor that is inhibited by several compounds. Farnesoid X receptor (FXR) activation also inhibits NTCP function.Approach and ResultsIn this study, we investigated the inhibitory effect of bile acid (BA) derivatives—namely obeticholic acid (OCA), 6α‐ethyl‐24‐nor‐5β‐cholane‐3α,7α,23‐triol‐23 sulfate sodium salt (INT‐767; a dual agonist of FXR and Takeda G protein‐coupled receptor [TGR5]), and 6α‐ethyl‐23(S)‐methyl‐cholic acid (INT‐777; a TGR5 agonist)—3‐(2,6‐dichlorophenyl)‐4‐(3′‐carboxy‐2‐chlorostilben‐4‐yl)oxymethyl‐5‐isopropylisoxazole (GW4064; a FXR agonist), cyclosporin A, and irbesartan. OCA and INT‐777 suppressed HBV infection in HepG2‐human NTCP‐C4 cells. Interestingly, INT‐767 showed potent inhibition by attaching to HBV particles rather than binding to NTCP. As an entry inhibitor, INT‐767 was stronger than various natural BAs. Furthermore, in chimeric mice with humanized liver, INT‐767 markedly delayed the initial rise of HBsAg, HBeAg, and HBV DNA and reduced covalently closed circular DNA. The strong inhibitory effect of INT‐767 may be due to the cumulative effect of its ability to inhibit the entry of HBV and to stimulate FXR downstream signaling, which affects the postentry step.ConclusionsOur results suggest that BA derivatives, particularly INT‐767, are prospective candidate anti‐HBV agents. Clarifying the underlying mechanisms of BA derivatives would facilitate the development of anti‐HBV agents.

01 Dec 2014·Clinical Gastroenterology and HepatologyQ1 · MEDICINE

The Fatty Acid–Bile Acid Conjugate Aramchol Reduces Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease

Q1 · MEDICINE

Article

Author: Mariana Yaron ; Emanuel Sikuler ; Mahmud Mahamid ; Meir Mizrahi ; Maya Halpern ; Saif Abu-Mouch ; Tuvia Gilat ; Nimmer Assy ; Annat Blank ; Dafna Ben Bashat ; Moshe Graif ; Alexander Fich ; Assaf Issachar ; Eli Zuckerman ; Rifaat Safadi ; Fred M. Konikoff ; Shira Zelber-Sagi ; Yaacov Baruch ; Alice Hershkovitz ; Yoav Lurie ; Ran Oren ; Naftali Stern ; Ziva Rosenthal-Galili

BACKGROUND & AIMSWe investigated the effects of the fatty acid-bile acid conjugate 3β-arachidyl-amido, 7α-12α-dihydroxy, 5β-cholan-24-oic acid (Aramchol; Trima Israel Pharmaceutical Products Ltd, Maabarot, Israel) in a phase 2 trial of patients with nonalcoholic fatty liver disease (NAFLD).METHODSWe performed a randomized, double-blind, placebo-controlled trial of 60 patients with biopsy-confirmed NAFLD (6 with nonalcoholic steatohepatitis) at 10 centers in Israel. Patients were given Aramchol (100 or 300 mg) or placebo once daily for 3 months (n = 20/group). The main end point was the difference between groups in the change in liver fat content according to magnetic resonance spectroscopy. The secondary end points focused on the differences between groups in alterations of liver enzyme levels, levels of adiponectin, homeostasis model assessment scores, and endothelial function.RESULTSNo serious or drug-related adverse events were observed in the 58 patients who completed the study. Over 3 months, liver fat content decreased by 12.57% ± 22.14% in patients given 300 mg/day Aramchol, but increased by 6.39% ± 36.27% in the placebo group (P = .02 for the difference between groups, adjusted for age, sex, and body mass index). Liver fat content decreased in the 100-mg Aramchol group, by 2.89% ± 28.22%, but this change was nonsignificant (P = .35), indicating a dose-response relationship (P for trend = .01). Groups given Aramchol had nonsignificant improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin, but homeostasis model assessment scores did not change. The appropriateness of a single daily dose was confirmed by pharmacokinetic analysis.CONCLUSIONSThree months' administration of the fatty acid-bile acid conjugate Aramchol is safe, tolerable, and significantly reduces liver fat content in patients with NAFLD. The reduction in liver fat content occurred in a dose-dependent manner and was associated with a trend of metabolic improvements, indicating that Aramchol might be used for the treatment of fatty liver disease. ClinicalTrials.gov number: NCT01094158.

100 Deals associated with FXR and TGR5 ligands 30(Università degli Studi di Napoli Federico II)

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FXR and TGR5 ligands 30(Università degli Studi di Napoli Federico II)

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation