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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

Abstract : 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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https://hal-univ-artois.archives-ouvertes.fr/hal-03185533
Contributor : Virginie Justin-Labonne <>
Submitted on : Tuesday, March 30, 2021 - 1:48:46 PM
Last modification on : Monday, July 19, 2021 - 2:06:03 PM

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Vanessa Hoguet, Manuel Lasalle, Mathieu Maingot, Geoffroy Dequirez, Rajaa Boulahjar, et al.. 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. Journal of Medicinal Chemistry, American Chemical Society, 2021, 64 (3), pp.1593-1610. ⟨10.1021/acs.jmedchem.0c01774⟩. ⟨hal-03185533⟩

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