Navigation in bile acid chemical space: discovery of novel FXR and GPBAR1 ligands.
Sci Rep
; 6: 29320, 2016 07 06.
Article
em En
| MEDLINE
| ID: mdl-27381677
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fármacos Gastrointestinais
/
Ácidos e Sais Biliares
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Receptores Citoplasmáticos e Nucleares
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Receptores Acoplados a Proteínas G
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article