Abstract
Bile acid (BA) receptors represent well-defined targets for the development of novel therapeutic approaches to metabolic and inflammatory diseases. In the present study, we report the generation of novel C-3 modified 6-ethylcholane derivatives. The pharmacological characterization and molecular docking studies for the structure-activity rationalization, allowed the identification of 3β-azido-6α-ethyl-7α-hydroxy-5β-cholan-24-oic acid (compound 2), a potent and selective FXR agonist with a nanomolar potency in transactivation assay and high efficacy in the recruitment of SRC-1 co-activator peptide in Alfa Screen assay. In vitro, compound 2 was completely inactive towards common off-targets such as the nuclear receptors PPARα, PPARγ, LXRα, and LXRβ and the membrane G-coupled BA receptor, GPBAR1. This compound when administered in vivo exerts a robust FXR agonistic activity increasing the liver expression of FXR-target genes including SHP, BSEP, OSTα, and FGF21, while represses the expression of CYP7A1 gene that is negatively regulated by FXR. Collectively these effects result in a significant reshaping of BA pool in mouse. In summary, compound 2 represents a promising candidate for drug development in liver and metabolic disorders.
Highlights
Bile acids (BAs), the end products of cholesterol metabolism, are increasingly recognized for their role as signaling molecules
The signaling pathways involve the interaction with several nuclear receptors (NRs) and cell surface G-protein-coupled receptors (G-PCRs), including the G proteincoupled bile acid receptor GPBAR1 (Maruyama et al, 2002; Kawamata et al, 2003; Fiorucci and Distrutti, 2015; Copple and Li, 2016)
GPBAR1 activation exerts useful pharmacological effects such as increased energy expenditure by brown and white adipose tissue, glucagon-like peptide 1 (GLP-1) secretion by intestinal endocrine cells which hold the potential for beneficial effects on glucose metabolism and insulin sensitivity
Summary
Bile acids (BAs), the end products of cholesterol metabolism, are increasingly recognized for their role as signaling molecules. GPBAR1 activation exerts useful pharmacological effects such as increased energy expenditure by brown and white adipose tissue, glucagon-like peptide 1 (GLP-1) secretion by intestinal endocrine cells which hold the potential for beneficial effects on glucose metabolism and insulin sensitivity (vanNierop et al, 2017; Hodge and Nunez, 2016). These findings have prompted the development of dual GPBAR1/FXR agonists as a new frontier in the pharmacological treatment of hypercholesterolemia, hypertriglyceridemia, and type II diabetes (Fiorucci et al, 2009; Fiorucci and Distrutti, 2015; Sepe et al, 2015b). These data, combined with the good pharmacokinetic behavior, affirm compound 2 as a new therapeutical opportunity for the treatment of liver FXR-mediated diseases
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