Discovery of LH10, a novel fexaramine-based FXR agonist for the treatment of liver disease

Huang, Wanqiu; Cao, Zhijun; Wang, Wenxin; Yang, Zhongcheng; Jiao, Shixuan; Chen, Ya; Chen, Siliang; Zhang, Luyong; Li, Zheng

doi:10.1016/j.bioorg.2023.107071

Cited by 5 publications

(23 citation statements)

References 61 publications

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“…However, the compounds 78 (with an EC50 > 10 µM) and 79 (with an EC50 of 3.87 µM) did not exhibit better performance compared to Fex (20) [40]. Nonetheless, they demonstrated superior activity compared to the corresponding methyl esters, 80 (with an EC50 of 9.58 µM) and 81 (with an EC50 > 10 µM) [40]. In a co-activator recruitment assay of hFGF19 and IBABP gene expression, BMS-986318 (74) exhibited increased potency and reduced efficacy when compared to GW4064 (1).…”

Section: Met409 (42) Is a Fex (20) Derived Fxr Agonist Developed By P...mentioning

confidence: 91%

“…To develop LH10 (82), modifications were made to the biphenyl moiety of Fex (20) by incorporating hydrophilic groups. The aim of these alterations was to enhance the compound's draggability [40]. However, it was observed that these modifications resulted in a significant decrease in activity (i.e., 75-77) (Table 2) [40].…”

Section: Met409 (42) Is a Fex (20) Derived Fxr Agonist Developed By P...mentioning

confidence: 99%

“…The aim of these alterations was to enhance the compound's draggability [40]. However, it was observed that these modifications resulted in a significant decrease in activity (i.e., 75-77) (Table 2) [40]. In a co-activator recruitment assay of hFGF19 and IBABP gene expression, BMS-986318 (74) exhibited increased potency and reduced efficacy when compared to GW4064 (1).…”

Section: Met409 (42) Is a Fex (20) Derived Fxr Agonist Developed By P...mentioning

confidence: 99%

“…This confirms the tissue-selective profile of BMS-986318 Collagen deposition induced by liver fibrosis was lowered in a dose-dependent manner, indicating the antifibrotic effects of BMS-986318 (74). LH10 (82) was designed by modifying two of the three main regions of Fex ( 20) (EC50 = 0.30 µM) to obtain higher activity (Table 2) [40]. While LH10 (82) showed higher activity overall (EC50 = 0.14 µM), it is important to note that this drug has not been tested for intestinal selectivity.…”

Section: Met409 (42) Is a Fex (20) Derived Fxr Agonist Developed By P...mentioning

confidence: 99%

“…LH10 (82) was then virtually docked into a crystal structure of FXR and compared to Fex (20). It was found that LH10 (82) occupies the same an EC50 > 10 µM) [40]. (20), showed improved activity by replacing the second phenyl ring of region 1 in 20 with benzoheterocycles and substituting region 2 of 20 with cyclopropyl pyrazolyl.…”

Section: Met409 (42) Is a Fex (20) Derived Fxr Agonist Developed By P...mentioning

confidence: 99%

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Tailoring FXR Modulators for Intestinal Specificity: Recent Progress and Insights

Morrison,

Elgendy

2024

Molecules

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While FXR has shown promise in regulating bile acid synthesis and maintaining glucose and lipid homeostasis, undesired side effects have been observed in clinical trials. To address this issue, the development of intestinally restricted FXR modulators has gained attention as a new avenue for drug design with the potential for safer systematic effects. Our review examines all currently known intestinally restricted FXR ligands and provides insights into the steps taken to enhance intestinal selectivity.

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Section: Met409 (42) Is a Fex (20) Derived Fxr Agonist Developed By P...mentioning

confidence: 91%

Section: Met409 (42) Is a Fex (20) Derived Fxr Agonist Developed By P...mentioning

confidence: 99%

Section: Met409 (42) Is a Fex (20) Derived Fxr Agonist Developed By P...mentioning

confidence: 99%

Section: Met409 (42) Is a Fex (20) Derived Fxr Agonist Developed By P...mentioning

confidence: 99%

Section: Met409 (42) Is a Fex (20) Derived Fxr Agonist Developed By P...mentioning

confidence: 99%

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Tailoring FXR Modulators for Intestinal Specificity: Recent Progress and Insights

Morrison,

Elgendy

2024

Molecules

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Immunology of bile acids regulated receptors

Fiorucci,

Marchianò,

Urbani

et al. 2024

Progress in Lipid Research

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Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Fleishman,

Kumar

2024

Sig Transduct Target Ther

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Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.

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Discovery of LH10, a novel fexaramine-based FXR agonist for the treatment of liver disease

Cited by 5 publications

References 61 publications

Tailoring FXR Modulators for Intestinal Specificity: Recent Progress and Insights

Tailoring FXR Modulators for Intestinal Specificity: Recent Progress and Insights

Immunology of bile acids regulated receptors

Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

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