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Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation

The farnesoid X receptor (FXR) is involved in glucose and lipid metabolism regulation, which makes it an attractive target for the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. In order to find novel FXR agonists, a structure-based pharmacophore model collection was develop...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2011-12, Vol.19 (23), p.7168-7180
Main Authors: Schuster, Daniela, Markt, Patrick, Grienke, Ulrike, Mihaly-Bison, Judit, Binder, Markus, Noha, Stefan M., Rollinger, Judith M., Stuppner, Hermann, Bochkov, Valery N., Wolber, Gerhard
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Language:English
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Summary:The farnesoid X receptor (FXR) is involved in glucose and lipid metabolism regulation, which makes it an attractive target for the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. In order to find novel FXR agonists, a structure-based pharmacophore model collection was developed and theoretically evaluated against virtual databases including the ChEMBL database. The most suitable models were used to screen the National Cancer Institute (NCI) database. Biological evaluation of virtual hits led to the discovery of a novel FXR agonist with a piperazine scaffold (compound 19) that shows comparable activity as the endogenous FXR agonist chenodeoxycholic acid (CDCA, compound 2).
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.09.056