Avicholic Acid: A Lead Compound from Birds on the Route to Potent TGR5 Modulators

  • ACS Med Chem Lett. 2012 Feb 6;3(4):273-7. doi: 10.1021/ml200256d.
Roberto Pellicciari  1 ,  Antimo Gioiello  1 ,  Paola Sabbatini  1 ,  Francesco Venturoni  1 ,  Roberto Nuti  1 ,  Carolina Colliva  2 ,  Giovanni Rizzo  3 ,  Luciano Adorini  3 ,  Mark Pruzanski  3 ,  Aldo Roda  2 ,  Antonio Macchiarulo  1
Affiliations
  • 1. Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia , Via del Liceo 1, 06123 Perugia, Italy.
  • 2. Dipartimento di Scienze Farmaceutiche, Alma Mater Studiorum, Università di Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
  • 3. Intercept Pharmaceuticals , New York, New York 10013, United States.
PMID: 24900463 DOI: 10.1021/ml200256d
Abstract

Grounding on our former 3D QSAR studies, a knowledge-based screen of natural Bile Acids from diverse animal species has led to the identification of avicholic acid as a selective but weak TGR5 agonist. Chemical modifications of this compound resulted in the disclosure of 6α-ethyl-16-epi-avicholic acid that shows enhanced potency at TGR5 and FXR receptors. The synthesis, biological appraisals, and structure-activity relationships of this series of compounds are herein described. Moreover, a thorough physicochemical characterization of 6α-ethyl-16-epi-avicholic acid as compared to naturally occurring Bile Acids is reported and discussed.

Keywords
16-epi-avicholic acid; CMC; FXR; TGR5; avicholic acid; bile acid; structure−activity relationship.