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

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.