Extending SAR of bile acids as FXR ligands: discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine

Antimo Gioiello; Antonio Macchiarulo; Andrea Carotti; Paolo Filipponi; Gabriele Costantino; Giovanni Rizzo; Luciano Adorini; Roberto Pellicciari

doi:10.1016/j.bmc.2011.03.004

Extending SAR of bile acids as FXR ligands: discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine

Bioorg Med Chem. 2011 Apr 15;19(8):2650-8. doi: 10.1016/j.bmc.2011.03.004. Epub 2011 Mar 10.

Authors

Antimo Gioiello¹, Antonio Macchiarulo, Andrea Carotti, Paolo Filipponi, Gabriele Costantino, Giovanni Rizzo, Luciano Adorini, Roberto Pellicciari

Affiliation

¹ Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Perugia, Italy.

PMID: 21459580
DOI: 10.1016/j.bmc.2011.03.004

Abstract

Within our efforts in the discovery of novel potent and selective ligands for the FXR receptor, 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine was synthesized and evaluated for its ability to activate and modulate the biological response of the receptor. Alphascreen and RT-PCR revealed that the 6α-ethyl-24-norcholanyl-23-amine derivate behaves as full FXR agonist endowed with high binding affinity and efficacy, representing a promising lead candidate for further optimization. In addition, docking studies provide new insights into the molecular basis governing the partial and full agonist activity at FXR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Acids and Salts / chemistry*
Computer Simulation
Drug Discovery
Gastrointestinal Agents
Ligands
Protein Binding
Receptors, Cytoplasmic and Nuclear / agonists*
Reverse Transcriptase Polymerase Chain Reaction
Structure-Activity Relationship

Substances

Bile Acids and Salts
Gastrointestinal Agents
Ligands
Receptors, Cytoplasmic and Nuclear
farnesoid X-activated receptor