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Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

TGR5

Mechanism

TGR5 agonists(G-protein coupled bile acid receptor 1 agonists)

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

Institut Pasteur de Lille

Active Organization

Institut Pasteur de Lille

Inactive Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC25H27ClN2O5

InChIKeyAARPMDPNSORGBN-UXHICEINSA-N

CAS Registry1872436-42-4

Author: Boulahjar, Rajaa ; Gosselet, Fabien ; Dorchies, Emilie ; Leroux, Florence ; Deprez-Poulain, Rebecca ; Villoutreix, Bruno O ; Duplan, Isabelle ; Baron, Morgane ; Hennuyer, Nathalie ; Staels, Bart ; Deprez, Benoit ; Descat, Amandine ; Lasalle, Manuel ; Sevin, Emmanuel ; Tailleux, Anne ; Dumont, Julie ; Culot, Maxime ; Picon, Sylvain ; Vallez, Emmanuelle ; Lestavel, Sophie ; Charton, Julie ; Chaput, Ludovic ; Piveteau, Catherine ; Touche, Véronique ; Hoguet, Vanessa ; Roussel, Pascal ; Lipka, Emmanuelle ; Biela, Alexandre

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.

100 Deals associated with 77-A

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