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
- 20 January 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 64 (3), 1593-1610
- https://doi.org/10.1021/acs.jmedchem.0c01774
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.Keywords
Funding Information
- Universit? de Lille (A007)
- Agence Nationale de la Recherche (ANR-10-LABX-46, ANR-17-CE14-0007-03)
- European Commission
- European Regional Development Fund (11003609)
- H2020 European Research Council (694717)
- SATT Nord (M0075/SATTNORD)
- Conseil Re?gional Nord-Pas de Calais
- Etat DRRT
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