Navigation in bile acid chemical space: Discovery of novel FXR and GPBAR1 ligands
| Autor: | Finamore, C, Festa, C, Renga, B, Sepe, V, Carino, A, Masullo, D, Biagioli, Michele, Marchianò, S, Capolupo, A, Monti, M, Fiorucci, Stefano, Zampella, A., Carino, Adriana |
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| Přispěvatelé: | Finamore, Claudia, Festa, Carmen, Renga, B, Sepe, Valentina, Carino, A, Masullo, Dario, Biagioli, M, Marchianò, S, Capolupo, A, Monti, Mc, Fiorucci, S, Zampella, Angela |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Agonist Cell signaling medicine.drug_class Druggability Receptors Cytoplasmic and Nuclear Pharmacology Article Receptors G-Protein-Coupled Bile Acids and Salts 03 medical and health sciences 0302 clinical medicine Gastrointestinal Agents medicine Humans Receptor Gastrointestinal agent Multidisciplinary Molecular Structure Bile acid Chemistry Hep G2 Cells HEK293 Cells 030104 developmental biology Biochemistry Nuclear receptor 030220 oncology & carcinogenesis Farnesoid X receptor |
| Zdroj: | Scientific Reports |
| Popis: | Bile acids are signaling molecules interacting with nuclear receptors and membrane G-protein-coupled receptors. Among these receptors, the farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) have gained increasing consideration as druggable receptors and their exogenous dual regulation represents an attractive strategy in the treatment of enterohepatic and metabolic disorders. However, the therapeutic use of dual modulators could be associated to severe side effects and therefore the discovery of selective GPBAR1 and FXR agonists is an essential step in the medicinal chemistry optimization of bile acid scaffold. In this study, a new series of 6-ethylcholane derivatives modified on the tetracyclic core and on the side chain has been designed and synthesized and their in vitro activities on FXR and GPBAR1 were assayed. This speculation resulted in the identification of compound 7 as a potent and selective GPBAR1 agonist and of several derivatives showing potent dual agonistic activity. |
| Databáze: | OpenAIRE |
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