更新于：2024-11-01

FXR x FABP1

更新于：2024-11-01

基本信息

关联

项与 FXR x FABP1 相关的药物

ZLY-28

靶点

FABP1 x FXR

作用机制

FABP1抑制剂 [+1]

在研机构

广东药科大学

原研机构

广东药科大学

在研适应症

代谢功能障碍相关的脂肪肝病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 FXR x FABP1 相关的临床结果

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100 项与 FXR x FABP1 相关的转化医学

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0 项与 FXR x FABP1 相关的专利（医药）

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项与 FXR x FABP1 相关的文献（医药）

2023-10-01·Biochemical Pharmacology

Development of bile acid activated receptors hybrid molecules for the treatment of inflammatory and metabolic disorders

Review

作者: Fiorillo, Bianca ; Distrutti, Eleonora ; Zampella, Angela ; Sepe, Valentina ; Biagioli, Michele ; Rapacciuolo, Pasquale ; Fiorucci, Stefano

The farnesoid-x-receptor (FXR) and the G protein bile acid activated receptor (GPBAR)1 are two bile acid activated receptors highly expressed in entero-hepatic, immune, adipose and cardiovascular tissues. FXR and GPBAR1 are clinically validated targets in the treatment of metabolic disorders and FXR agonists are currently trialled in patients with non-alcoholic steato-hepatitis (NASH). Results of these trials, however, have raised concerns over safety and efficacy of selective FXR ligands suggesting that the development of novel agent designed to impact on multiple targets might have utility in the treatment of complex, multigenic, disorders. Harnessing on FXR and GPBAR1 agonists, several novel hybrid molecules have been developed, including dual FXR and GPBAR1 agonists and antagonists, while exploiting the flexibility of FXR agonists toward other nuclear receptors, dual FXR and peroxisome proliferators-activated receptors (PPARs) and liver-X-receptors (LXRs) and Pregnane-X-receptor (PXR) agonists have been reported. In addition, modifications of FXR agonists has led to the discovery of dual FXR agonists and fatty acid binding protein (FABP)1 and Leukotriene B4 hydrolase (LTB4H) inhibitors. The GPBAR1 binding site has also proven flexible to accommodate hybrid molecules functioning as GPBAR1 agonist and cysteinyl leukotriene receptor (CYSLTR)1 antagonists, as well as dual GPBAR1 agonists and retinoid-related orphan receptor (ROR)γt antagonists, dual GPBAR1 agonist and LXR antagonists and dual GPBAR1 agonists endowed with inhibitory activity on dipeptidyl peptidase 4 (DPP4). In this review we have revised the current landscape of FXR and GPBAR1 based hybrid agents focusing on their utility in the treatment of metabolic associated liver disorders.

2023-05-11·Journal of medicinal chemistry1区 · 医学

Discovery of the First-in-Class Intestinal Restricted FXR and FABP1 Dual Modulator ZLY28 for the Treatment of Nonalcoholic Fatty Liver Disease.

1区 · 医学

Article

作者: Wang, Bin ; Cao, Zhijun ; Wang, Wenxin ; Jiao, Shixuan ; Chen, Siliang ; Huang, Wanqiu ; Cai, Zongyu ; Hu, Lijun ; Deng, Liming ; Ren, Qiang ; Zhou, Zongtao ; Li, Zheng ; Yang, Zhongcheng ; Zhang, Luyong ; Chen, Ya

The prevalence of nonalcoholic steatohepatitis (NASH) is increasing rapidly worldwide, and NASH has become a serious problem for human health. Recently, the selective activation of the intestinal farnesoid X receptor (FXR) was considered as a more promising strategy for the treatment of NASH with lesser side effects due to reduced systemic exposure. Moreover, the inhibition of intestinal fatty acid binding protein 1 (FABP1) alleviated obesity and NASH by reducing dietary fatty acid uptake. In this study, the first-in-class intestinal restricted FXR and FABP1 dual-target modulator ZLY28 was discovered by comprehensive multiparameter optimization studies. The reduced systemic exposure of ZLY28 might provide better safety by decreasing the on- and off-target side effects in vivo. In NASH mice, ZLY28 exerted robust anti-NASH effects by inhibiting FABP1 and activating the FXR-FGF15 signaling pathway in the ileum. With the above attractive efficacy and preliminary safety profiles, ZLY28 is worthy of further evaluation as a novel anti-NASH agent.

2020-06-01·Liver International2区 · 医学

Absence of Bsep/Abcb11 attenuates MCD diet‐induced hepatic steatosis but aggravates inflammation in mice

2区 · 医学

Article

作者: Trauner, Michael ; Krivanec, Sebastian ; Steinacher, Daniel ; Claudel, Thierry ; Wahlström, Annika ; Fuchs, Claudia D. ; Marschall, Hanns‐Ulrich ; Stojakovic, Tatjana ; Scharnagl, Hubert ; Stahlman, Marcus ; Mlitz, Veronika

AbstractBackgroundBile acids (BAs) regulate hepatic lipid metabolism and inflammation. Bile salt export pump (BSEP) KO mice are metabolically preconditioned with a hydrophilic BA composition protecting them from cholestasis. We hypothesize that changes in hepatic BA profile and subsequent changes in BA signalling may critically determine the susceptibility to steatohepatitis.MethodsWild‐type (WT) and BSEP KO mice were challenged with methionine choline‐deficient (MCD) diet to induce steatohepatitis. Serum biochemistry, lipid profiling as well as intestinal lipid absorption were assessed. Markers of inflammation, fibrosis, lipid and BA metabolism were analysed. Hepatic and faecal BA profile as well as serum levels of the BA synthesis intermediate 7‐hydroxy‐4‐cholesten‐3‐one (C4) were also investigated.ResultsBile salt export pump KO MCD‐fed mice developed less steatosis but more inflammation than WT mice. Intestinal neutral lipid levels were reduced in BSEP KO mice at baseline and under MCD conditions. Faecal non‐esterified fatty acid concentrations at baseline and under MCD diet were markedly elevated in BSEP KO compared to WT mice. Serum liver enzymes and hepatic expression of inflammatory markers were increased in MCD‐fed BSEP KO animals. PPARα protein levels were reduced in BSEP KO mice. Accordingly, PPARα downstream targets Fabp1 and Fatp5 were repressed, while NFκB subunits were increased in MCD‐fed BSEP KO mice. Farnesoid X receptor (FXR) protein levels were reduced in MCD‐fed BSEP KO vs WT mice. Hepatic BA profile revealed elevated levels of TβMCA, exerting FXR antagonistic action, while concentrations of TCA (FXR agonistic function) were reduced.ConclusionPresence of hydroxylated BAs result in increased faecal FA excretion and reduced hepatic lipid accumulation. This aggravates development of MCD diet‐induced hepatitis potentially by decreasing FXR and PPARα signalling.