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

被引：11

作者：

Hoguet, Vanessa ^{[1
]}

Lasalle, Manuel ^{[1
]}

Maingot, Mathieu ^{[1
]}

Dequirez, Geoffroy ^{[1
]}

Boulahjar, Rajaa ^{[1
]}

Leroux, Florence ^{[2
]}

Piveteau, Catherine ^{[1
]}

Herledan, Adrien ^{[1
]}

Biela, Alexandre ^{[1
]}

Dumont, Julie ^{[1
]}

Chavez-Talavera, Oscar ^{[3
]}

Belloy, Loic ^{[3
]}

Duplan, Isabelle ^{[3
]}

Hennuyer, Nathalie ^{[3
]}

Butruille, Laura ^{[3
]}

Lestavel, Sophie ^{[3
]}

Sevin, Emmanuel ^{[4
]}

Culot, Maxime ^{[4
]}

Gosselet, Fabien ^{[4
]}

Staels, Bart ^{[3
]}

Deprez, Benoit ^{[2
]}

Tailleux, Anne ^{[3
]}

Charton, Julie ^{[2
]}

机构：

[1] Univ Lille, Inst Pasteur Lille, INSERM, U1177,Drugs & Mol Living Syst, F-59000 Lille, France

[2] Univ Lille, Inst Pasteur Lille, EGID, INSERM,U1177,Drugs & Mol Living Syst, F-59000 Lille, France

[3] Univ Lille, Inst Pasteur Lille, CHU Lille, INSERM,U1011,EGID, F-59000 Lille, France

[4] Univ Artois, Blood Brain Barrier Lab LBHE, UR 2465, F-62300 Lens, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 03期

基金：

欧洲研究理事会;

关键词：

D O I：

10.1021/acs.jmedchem.0c01774

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1593 / 1610

页数：18

共 1 条

[1] Discovery, Structure-Activity Relationships, and In Vivo Activity of Dihydropyridone Agonists of the Bile Acid Receptor TGR5
Picon, Sylvain
Boulahjar, Rajaa
Hoguet, Vanessa
Baron, Morgane
Duplan, Isabelle
Vallez, Emmanuelle
Hennuyer, Nathalie
Dumont, Julie
Touche, Veïronique
Dorchies, Emilie
Lasalle, Manuel
Descat, Amandine
Piveteau, Catherine
Biela, Alexandre
Chaput, Ludovic
Villoutreix, Bruno O.
Lipka, Emmanuelle
Sevin, Emmanuel
Culot, Maxime
Gosselet, Fabien
Lestavel, Sophie
Roussel, Pascal
Deprez-Poulain, Rebecca
Leroux, Florence
Staels, Bart
Deprez, Benoit
Tailleux, Anne
Charton, Julie
JOURNAL OF MEDICINAL CHEMISTRY, 2023, 66 (17) : 11732 - 11760

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