Vildagliptin-Derived Dipeptidyl Peptidase 9 (DPP9) Inhibitors: Identification of a DPP8/9-Specific Lead.
ChemMedChem
; 17(15): e202200097, 2022 08 03.
Article
em En
| MEDLINE
| ID: mdl-35760756
ABSTRACT
Vildagliptin is a marketed DPP4 inhibitor, used in the management of type 2 diabetes. The molecule also has notable DPP8/9 affinity, with some preference for DPP9. Therefore, we aimed to use vildagliptin as a starting point for selective DPP8/9 inhibitors, and to engineer out the parent compound's DPP4-affinity. In addition, we wanted to identify substructures in the obtained molecules that allow their further optimization into inhibitors with maximal DPP9 selectivity. Various 2S-cyanopyrrolidines and isoindoline were investigated as P1 residues of vildagliptin analogs. The obtained set was expanded with derivatives bearing O-substituted, N-(3-hydroxyadamantyl)glycine moieties at the P2 position. In this way, representatives were discovered with DPP8/9 potencies comparable to the parent molecule, but with overall selectivity towards DPP4, DPP2, FAP, and PREP. Furthermore, the most promising molecules in this series have a 4- to 7-fold preference for DPP9 over DPP8. Finally, a molecular dynamics study was carried out to maximize our insight into experimental selectivity data.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus Tipo 2
/
Dipeptidases
/
Inibidores da Dipeptidil Peptidase IV
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article