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@mail :  manuel.lasalle@etu.univ-lille2.fr      tél. :  0320964006

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Titre de la communication :
Optimization and development of novel agonists of the bile acid receptor TGR5 for treatment of diabetes mellitus and associated metabolic diseases.
Auteurs (et leurs adresses) de la communication :
Manuel Lasalle (a), Anne Tailleux (b), Nathalie Hennuyer (b), Barbara Dubanchet (b), Loic Belloy (b), Florence Leroux (a), Bart Staels (b), Benoit Deprez (a), Hélène Gras-Masse (a), Julie Charton (a). (a) INSERM U761 (b) INSERM U1011
Résumé de la communication :
Bile acids are natural derivatives of cholesterol that have been first discovered as lipid solubilizing agents participating in the digestion process. But several evidences have shown in the past decades that bile acids also have signaling effects. To date, two receptors are known to be sensitive to bile acids: FXR, a nuclear receptor that is thought to play a critical role in bile acid metabolism, and the GPCR TGR5. TGR5 is a ubiquitous GPCR sensitive to bile acids. It is mostly expressed in the liver, the gall bladder, the nervous system, some immune cells, and in the intestine where it is expressed at the membrane of enteroendocrine L cells. Activation of TGR5 in these cells increases the secretion of GLP1, an incretin hormone known to have a good potential in the treatment of diabetes mellitus, as exemplified by the two incretin-related classes of drugs (gliptines and long-lasting GLP1 agonist peptides). Therefore, pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity.
Nevertheless, recent experiments have also shown that activation of TGR5 by systemic agonists in mouse models could induce hyperplasia of the gall bladder. It has also been reported that some systemic TGR5 agonists could trigger itching, and even in some cases cardiac dysfunction.
We have hypothesized that a selective activation of TGR5 limited to the intestine without systemic exposition would be powerful enough to obtain beneficial effect on glucose homeostasis via GLP1 secretion, while preventing potential adverse effects.
To that end, modification of a potent TGR5 agonist in a way that could prevent its intestinal absorption would lead to a compound that could be administrated per os with a higher safety profile compare to a systemic one.
Using the SAR produced until now on our TGR5 agonists series, we identified positions on our compounds that can be used to put some structural elements to prevent systemic exposure. Such modified analogues, exhibiting low caco-2 permeability, while keeping nanomolar potencies on both human and murine receptors and promoting potent GLP1 secretion in vitro are expected to give high concentration on the desired tissues (intestine) with systemic exposure severely restricted. They should therefore trigger the expected incretin effect in vivo without the side effects observed with systemic TGR5 agonists. One of our compounds has recently been evaluated in vivo in mice and allowed stimulation of the GLP1 secretion by a factor 4 compared to the vehicle group. In cellulo and in vivo characterization of some of our topical TGR5 agonists has thereby validated the interest of their oral administration to animals in order to establish proof of concept for the effect of non absorbed TGR5 agonists on glucose and energy homeostasis.
Here we describe the design, synthesis and characterization issues of such compounds as well as their pharmacological and ADME evaluation, in cellulo and in vivo.