Over the past two decades, synthetic FFAR1 agonists such as TAK-875 and TSL1806 have undergone meticulous design and extensive clinical trials. However, due to issues primarily related to hepatotoxicity, no FFAR1 agonist has yet received regulatory approval. Research into the sources of hepatotoxicity suggests that one potential cause lies in the molecular structure itself. These structures typically feature lipid-like carboxylic acid head groups, which tend to generate toxic metabolites. Strategies to mitigate these risks focus on optimizing chemical groups to reduce lipophilicity and prevent the formation of reactive metabolites. Recent studies have concentrated on developing low-molecular-weight compounds that more closely resemble natural products, with CPL207280 showing promising potential and liver safety, currently in Phase II clinical trials. Moreover, ongoing research continues to explore the potential applications of FFAR1 agonists in diabetes management, as well as in conditions such as non-alcoholic fatty liver disease (NAFLD) and cerebrovascular diseases. Utilizing advanced technologies such as artificial intelligence and computer-aided design, the development of compact molecules that mimic natural structures represents a hopeful direction for future research and development.
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http://dx.doi.org/10.2147/DDDT.S487469 | DOI Listing |
Drug Des Devel Ther
December 2024
Tasly Academy, Tasly Pharma Co., Ltd., Tianjin, People's Republic of China.
Over the past two decades, synthetic FFAR1 agonists such as TAK-875 and TSL1806 have undergone meticulous design and extensive clinical trials. However, due to issues primarily related to hepatotoxicity, no FFAR1 agonist has yet received regulatory approval. Research into the sources of hepatotoxicity suggests that one potential cause lies in the molecular structure itself.
View Article and Find Full Text PDFFood Chem
February 2025
Department of Food Science and Biotechnology, Ewha Womans University, Seoul 03760, Republic of Korea. Electronic address:
The physiological functions of various fatty acid-originating metabolites from foods and fermented products remained mostly untouched. Thereby, this study examined the biological activities of hydroxy fatty acids as agonists of G protein-coupled receptors (i.e.
View Article and Find Full Text PDFNat Commun
November 2024
Department of Computer Science, Stanford University, Stanford, CA, USA.
The goal of designing safer, more effective drugs has led to tremendous interest in molecular mechanisms through which ligands can precisely manipulate the signaling of G-protein-coupled receptors (GPCRs), the largest class of drug targets. Decades of research have led to the widely accepted view that all agonists-ligands that trigger GPCR activation-function by causing rearrangement of the GPCR's transmembrane helices, opening an intracellular pocket for binding of transducer proteins. Here we demonstrate that certain agonists instead trigger activation of free fatty acid receptor 1 by directly rearranging an intracellular loop that interacts with transducers.
View Article and Find Full Text PDFBiomed Pharmacother
December 2024
College of Pharmacy, Dongguk University-Seoul, Goyang-si, Kyeonggi-do 10326, Republic of Korea. Electronic address:
Fasiglifam, a candidate targeting GPR40, showed efficacy in clinical trials for type 2 diabetes but exerted liver toxicity. This study investigated the drug-induced liver injury (DILI) risk of Xelaglifam, a new GPR40 agonist, based on the potential toxicity mechanism of Fasiglifam; transporter inhibition, mitochondrial dysfunction, reactive metabolite formation, and covalent binding to proteins. In the hepatobiliary transporter assay, Xelaglifam showed a broader safety margin (>10-fold) against bile acid transporters, suggesting its less likelihood to cause bile acids accumulation, unlike Fasiglifam (<10-fold safety margin).
View Article and Find Full Text PDFInt J Mol Sci
October 2024
Istituto Superiore di Sanità, National Centre for Drug Research and Evaluation, Viale Regina Elena 299, 00161 Rome, Italy.
Free fatty acid receptor 1 (FFAR1) has emerged as the most targeted isoform of the free fatty acid receptors because of its involvement in the modulation of energy balance and its potential role in the control of inflammatory and pain conditions. Quercetin-3-oleate (AV2), recognized as a new FFAR1 partial agonist, was investigated for its ability to modulate inflammation and nociception. Human immortal neuroblastoma SH and the murine macrophagic RAW 264.
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