Free fatty acid receptor 4 (FFA4) has been recognized as an attractive target in metabolic diseases. To find potent and selective FFA4 agonist, 28 compounds of 3-(4-(phenoxymethyl)phenyl)propanoic acid and N-phenylbenzenesulfonamide derivatives were designed and synthesized, featuring OC and SO2-N linkage. For the OC linkage compounds, 1g showed the most potent FFA4 agonistic activity with a pEC of 5.81 ± 0.04 and exhibited at least 64-fold selectivity against FFA1. For SO2-N linkage agonists, 2m had a pEC of 5.66 ± 0.04 and displayed>46-fold selectivity against FFA1. Among these two series of compounds, 1g was the most potent agonist at FFA4 and the best selectivity against FFA1, demonstrated by docking simulation. Moreover, 1g showed receptor selectivity on other seven GPCRs. In anti-diabetic evaluation, 1g dose-dependently reduced blood glucose, which was better than a clinical phase III drug TAK875. This study provides guidance for FFA4 ligand design and drug optimization.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2020.127650 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT.
Cancer Cell Int
June 2023
Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University Health Sciences Center, Mercer University, 3001, Mercer University Drive, Atlanta, GA, 30341, USA.
Background: Papillary renal cell carcinoma (pRCC) is a highly metastatic genitourinary cancer and is generally irresponsive to common treatments used for the more prevalent clear-cell (ccRCC) subtype. The goal of this study was to examine the novel role of the free fatty-acid receptor-1 (FFA1/GPR40), a cell-surface expressed G protein-coupled receptor that is activated by medium-to-long chained dietary fats, in modulation of pRCC cell migration invasion, proliferation and tumor growth.
Methods: We assessed the expression of FFA1 in human pRCC and ccRCC tumor tissues compared to patient-matched non-cancerous controls, as well as in RCC cell lines.
Discovery of a structurally novel, potent, and once-weekly free fatty acid receptor 1 agonist for the treatment of diabetes.
Eur J Med Chem
January 2023
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China. Electronic address:
Type 2 diabetes mellitus (T2DM) is a lifelong disease that requires long-term medication to control glucose levels, and thereby long-acting drug has been clinically needed for improving medical adherence. The free fatty acid receptor 1 (FFA1) was considered as a promising target for several diseases, such as T2DM, pain and fatty liver. However, no once-weekly FFA1 agonist has been reported until now.
View Article and Find Full Text PDFIn Silico Searching for Alternative Lead Compounds to Treat Type 2 Diabetes through a QSAR and Molecular Dynamics Study.
Pharmaceutics
January 2022
Departamento Académico de Química Inorgánica, Facultad de Química e Ingeniería Química, Universidad Nacional Mayor de San Marcos, Cercado de Lima 15081, Peru.
Free fatty acid receptor 1 (FFA1) stimulates insulin secretion in pancreatic β-cells. An advantage of therapies that target FFA1 is their reduced risk of hypoglycemia relative to common type 2 diabetes treatments. In this work, quantitative structure-activity relationship (QSAR) approach was used to construct models to identify possible FFA1 agonists by applying four different machine-learning algorithms.
View Article and Find Full Text PDFExperimental and Emerging Free Fatty Acid Receptor Agonists for the Treatment of Type 2 Diabetes.
Medicina (Kaunas)
January 2022
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, School of Medicine, University of Palermo, 90133 Palermo, Italy.
The current management of Type 2 Diabetes Mellitus (T2DM) includes incretin-based treatments able to enhance insulin secretion and peripheral insulin sensitivity as well as improve body mass, inflammation, plasma lipids, blood pressure, and cardiovascular outcomes. Dietary Free Fatty Acids (FFA) regulate metabolic and anti-inflammatory processes through their action on incretins. Selective synthetic ligands for FFA1-4 receptors have been developed as potential treatments for T2DM.
View Article and Find Full Text PDFDesign, synthesis, and biological evaluation of novel dual FFA1 and PPARδ agonists possessing phenoxyacetic acid scaffold.
Bioorg Med Chem
February 2022
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; National Key Clinical Department (Clinical Pharmacy), The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address:
The free fatty acid receptor 1 (FFA1/GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have been widely considered as promising targets for type 2 diabetes mellitus (T2DM) due to their respective roles in promoting insulin secretion and improving insulin sensitivity. Hence, the dual FFA1/PPARδ agonists may exert synergistic effects by simultaneously activating FFA1 and PPARδ. The present study performed systematic exploration around previously reported FFA1 agonist 2-(2-fluoro-4-((2'-methyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)acetic acid (lead compound), leading to the identification of a novel dual FFA1/PPARδ agonist 2-(2-fluoro-4-((3-(6-methoxynaphthalen-2-yl)benzyl)oxy)phenoxy)acetic acid (the optimal compound), which displayed high selectivity over PPARα and PPARγ.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!