2. Academic Validation
  3. Discovery, Structure-Activity Relationships, and In Vivo Activity of Dihydropyridone Agonists of the Bile Acid Receptor TGR5

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

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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