Discovery of potent, selective, and orally bioavailable quinoline-based dipeptidyl peptidase IV inhibitors targeting Lys554.
Bioorg Med Chem
; 19(15): 4482-98, 2011 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-21741847
ABSTRACT
Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl]piperazine-2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC50=1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
/
Dipeptidil Peptidase 4
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Diabetes Mellitus Tipo 2
/
Inibidores da Dipeptidil Peptidase IV
/
Hipoglicemiantes
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Japão