Discovery of potent dipeptidyl peptidase IV inhibitors through pharmacophore hybridization and hit-to-lead optimization.
Bioorg Med Chem
; 21(7): 1749-55, 2013 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-23434133
ABSTRACT
A novel dipeptidyl peptidase IV inhibitor hit (5, IC50=0.86 µM) was structurally derived from our recently disclosed preclinical candidate 4 by replacing the cyanobenzyl with a butynyl based on pharmacophore hybridization. A hit-to-lead optimization effort was then initiated to improve its potency. Most N-substituted analogs exhibited good in vitro activity, and compound 18o (IC50=1.55 nM) was identified to be a potent dipeptidyl peptidase IV inhibitor with a significantly improved pharmacokinetic properties (bioavailablity 41% vs 82.9%; T1/2 2h vs 4.9h).
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Dipeptidil Peptidase 4
/
Inibidores da Dipeptidil Peptidase IV
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article