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Beyond the Rule of 5: Impact of PEGylation with Various Polymer Sizes on Pharmacokinetic Properties, Structure–Properties Relationships of mPEGylated Small Agonists of TGR5 Receptor

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Hoguet, Vanessa | Lasalle, Manuel | Maingot, Mathieu | Dequirez, Geoffroy | Boulahjar, Rajaa | Leroux, Florence | Piveteau, Catherine | Herledan, Adrien | Biela, Alexandre | Dumont, Julie | Chávez-Talavera, Oscar | Belloy, Loïc | Duplan, Isabelle | Hennuyer, Nathalie | Butruille, Laura | Lestavel, Sophie | Sevin, Emmanuel | Culot, Maxime | Gosselet, Fabien | Staels, Bart | Deprez, Benoit | Tailleux, Anne | Charton, Julie

Edité par CCSD ; American Chemical Society -

International audience. PEGylation of therapeutic agents is known to improve the pharmacokinetic behavior of macromolecular drugs and nanoparticles. In this work, we performed the conjugation of polyethylene glycols (220-5000 Da) to a series of non-steroidal small agonists of the bile acids receptor TGR5. A suitable anchoring position on the agonist was identified to retain full agonistic potency with the conjugates. We describe herein an extensive structure-properties relationships study allowing us to finely describe the non-linear effects of the PEG length on the physicochemical as well as the in vitro and in vivo pharmacokinetic properties of these compounds. When appending a PEG of suitable length to the TGR5 pharmacophore, we were able to identify either systemic or gut lumen-restricted TGR5 agonists.

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