Prodrugs of E-selectin Antagonists with Enhanced Pharmacokinetic Properties.
ChemMedChem
; 17(1): e202100634, 2022 01 05.
Article
em En
| MEDLINE
| ID: mdl-34870892
ABSTRACT
Because of their large polar surface area, carbohydrates often exhibit insufficient pharmacokinetic properties. Specifically, the carboxylic acid function of the tetrasaccharide sialyl Lewisx , a pharmacophore crucial for the formation of a salt bridge with selectins, prevents oral availability. A common approach is the transfer of carboxylic acid into ester prodrugs. Once the prodrug is either actively or passively absorbed, the active principle is released by hydrolysis. In the present study, ester prodrugs of selectin antagonists with aliphatic promoieties were synthesized and their potential for oral availability was investigated inâ
vitro and inâ
vivo. The addition of lipophilic ester moieties to overcome insufficient lipophilicity improved passive permeation into enterocytes, however at the same time supported efflux back to the small intestines as well as oxidation into non-hydrolysable metabolites. In summary, our examples demonstrate that different modifications of carbohydrates can result in opposing effects and have to be studied in their entirety.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
/
Selectina E
/
Ésteres
Limite:
Animals
/
Female
/
Humans
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Male
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article