期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 10, 页码 4185-4211出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01873
关键词
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资金
- INSERM, Universite de Lille, Institut Pasteur de Lille
- Conseil Regional Nord Pas de Calais
- ERDF [11003609]
- Etat DRRT
- European Genomic Institute for Diabetes (EGID) [ANR-10-LABX-46]
- European Research Council (ERC Grant Immunobile) [694717]
- European Commission
- Universite Lille 2 [A007]
- INSERM
- SATT Nord [M0075/SATTNORD]
- French Ministere de la Recherche
The role of the G-protein-coupled bile acid receptor TGRS in various organs, tissues, and cell types; specifically in intestinal endocrine L-cells and brown adipose tissue, has made it a promising therapeutical target in several diseases, especially type-2 diabetes and metabolic syndrome. However, recent studies have shown deleterious on-target effects of systemic TGRS agonists. To avoid these. systemic effects while stimulating glucagon-like peptide-1 (GLP-1) secreting enteroendocrine L-cells, we have designed TGRS agonists with low intestinal petmeability. In this article, we describe their synthesis, characterization, and biological evaluation. Among them, compound 24 is a potent GLP-1 secretagogue, has low effect on gallbladder volume, and improves glucose homeostasis in a preclinical murine model of diet-induced obesity and insulin resistance, making the proof of concept of the potential of topical intestinal TGR5 agonists as therapeutic agents in type-2 diabetes.
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