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Special Issue "Drug Development Targeting the Metabolic Nuclear Receptors: Recent Advances"

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State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2A Nan Wei Road, Beijing 100050, China
Interests: medicinal chemistry; chemical biology; natural products chemistry; drug discovery; anticancer agent; neurodegenerative disease therapeutics; metabolic disease therapeutics
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Prof. Dr. Haixia Chen

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Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
Interests: natural product; isolation; structure identification; physicochemical properties; bioactivity; structure-activity relationship; mechanism
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Dear Colleagues,

The metabolic nuclear receptors (NRs) consist of a subset of NR superfamily transcription factors. The activity of many NRs is modulated by lipophilic structurally diverse small molecules as internal ligands. Metabolic NR ligands not only serve biological studies, and are also applicable to the prevention or therapy of metabolic diseases e.g. insulin resistance and type II diabetes, hyperlipidemia and atherosclerosis, and more recently, non-alcohol fatty liver disease (NAFL) and non-alcohol steatohepatisis (NASH). The modulation of metabolic NRs even benefits the improvement of non-metabolic diseases such as liver, kidney or digestive tract diseases, cancer, viral infection, among others. This metabolic NR special issue aims to reflect the current status and recent progress in the chemical and/or pharmacological studies of natural and unnatural NR ligands, with an emphasis on the drug discovery and development efforts for various diseases through targeting different metabolic NRs.

Prof. Dr. Weishuo Fang
Prof. Dr. Haixia Chen
Guest Editors

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Keywords

nuclear receptor
metabolic diseases
type II diabetes
NASH
hyperlipidemia

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26 pages, 3952 KiB

Open AccessArticle

Structure Optimization of 12β-O-γ-Glutamyl Oleanolic Acid Derivatives Resulting in Potent FXR Antagonist/Modulator for NASH Therapy

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Pharmaceuticals 2023, 16(5), 758; https://doi.org/10.3390/ph16050758 - 17 May 2023

Cited by 2 | Viewed by 1193

Abstract

The farnesoid X receptor (FXR) plays a crucial role in regulating the metabolism of bile acids, lipids, and sugars. Consequently, it is implicated in the treatment of various diseases, including cholestasis, diabetes, hyperlipidemia, and cancer. The advancement of novel FXR modulators holds immense importance, especially in managing metabolic disorders. In this study, a series of oleanolic acid (OA) derivatives bearing 12β-O-(γ-glutamyl) groups were designed and synthesized. Using a yeast one-hybrid assay, we established a preliminary structure–activity relationship (SAR) and identified the most potent compound, 10b, which selectively antagonizes FXR over other nuclear receptors. Compound 10b can differentially modulate the downstream genes of FXR, including with the upregulation of the CYP7A1 gene. In vivo testing revealed that 10b (100 mg·Kg⁻¹) not only effectively inhibits lipid accumulation in the liver but also prevents liver fibrosis in both BDL rats and HFD mice. Molecular modeling indicated that the branched substitution of 10b extends into the H11–H12 region of FXR-LBD, possibly accounting for its CYP7A1 upregulation, which is different from a known OA 12β-alkonate. These findings suggest that 12-glutamyl OA derivative 10b represents a promising candidate for the treatment of nonalcoholic steatohepatitis (NASH). Full article

(This article belongs to the Special Issue Drug Development Targeting the Metabolic Nuclear Receptors: Recent Advances)

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Special Issue "Drug Development Targeting the Metabolic Nuclear Receptors: Recent Advances"

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