Discovery, Structure-Activity Relationships, and In Vivo Activity of Dihydropyridone Agonists of the Bile Acid Receptor TGR5

  • J Med Chem. 2023 Sep 14;66(17):11732-11760. doi: 10.1021/acs.jmedchem.2c01881.
Sylvain Picon  1 ,  Rajaa Boulahjar  1 ,  Vanessa Hoguet  1 ,  Morgane Baron  2 ,  Isabelle Duplan  2 ,  Emmanuelle Vallez  2 ,  Nathalie Hennuyer  2 ,  Julie Dumont  1  3 ,  Véronique Touche  2 ,  Emilie Dorchies  2 ,  Manuel Lasalle  1 ,  Amandine Descat  1 ,  Catherine Piveteau  1 ,  Alexandre Biela  1 ,  Ludovic Chaput  1 ,  Bruno O Villoutreix  1 ,  Emmanuelle Lipka  4 ,  Emmanuel Sevin  5 ,  Maxime Culot  5 ,  Fabien Gosselet  5 ,  Sophie Lestavel  2 ,  Pascal Roussel  6 ,  Rebecca Deprez-Poulain  7 ,  Florence Leroux  7  3 ,  Bart Staels  2 ,  Benoit Deprez  7  3 ,  Anne Tailleux  2 ,  Julie Charton  7
Affiliations
  • 1. Univ. Lille, Inserm, Institut Pasteur de Lille, U1177─Drugs and Molecules for Living Systems, F-59000 Lille, France.
  • 2. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
  • 3. Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41─UAR 2014─PLBS, F-59000 Lille, France.
  • 4. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167─RID-AGE─Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000 Lille, France.
  • 5. Univ. Artois, UR 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), F-62300 Lens, France.
  • 6. Univ. Lille, CNRS, Centrale Lille, Univ. Artois, UMR 8181─UCCS─Unité de Catalyse et Chimie du Solide, F-59000 Lille, France.
  • 7. Univ. Lille, Inserm, Institut Pasteur de Lille, U1177─Drugs and Molecules for Living Systems, EGID, F-59000 Lille, France.
PMID: 37639383 DOI: 10.1021/acs.jmedchem.2c01881
Abstract

A novel series of potent agonists of the bile acid receptor TGR5 bearing a dihydropyridone scaffold was developed from a high-throughput screen. Starting from a micromolar hit compound, we implemented an extensive structure-activity-relationship (SAR) study with the synthesis and biological evaluation of 83 analogues. The project culminated with the identification of the potent nanomolar TGR5 agonist 77A. We report the GLP-1 secretagogue effect of our lead compound ex vivo in mouse colonoids and in vivo. In addition, to identify specific features favorable for TGR5 activation, we generated and optimized a three-dimensional quantitative SAR model that contributed to our understanding of our activity profile and could guide further development of this dihydropyridone series.

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