Identification of novel uracil derivatives incorporating benzoic acid moieties as highly potent Dipeptidyl Peptidase-IV inhibitors.
Bioorg Med Chem
; 27(4): 644-654, 2019 02 15.
Article
em En
| MEDLINE
| ID: mdl-30642693
ABSTRACT
Dipeptidyl Peptidase-IV (DPP-4) is a validated therapeutic target for type 2 diabetes. Aiming to interact with both residues Try629 and Lys554 in S2' site, a series of novel uracil derivatives 1a-l and 2a-i incorporating benzoic acid moieties at the N3 position were designed and evaluated for their DPP-4 inhibitory activity. Structure-activity relationships (SAR) study led to the identification of the optimal compound 2b as a potent and selective DPP-4 inhibitor (IC50â¯=â¯1.7â¯nM). Docking study revealed the additional salt bridge formed between the carboxylic acid and primary amine of Lys554 has a key role in the enhancement of the activity. Furthermore, compound 2b exhibited no cytotoxicity in human hepatocyte LO2 cells up to 50⯵M. Subsequent in vivo evaluations revealed that the ester of 2b robustly improves the glucose tolerance in normal mice. The overall results have shown that compound 2b has the potential to a safe and efficacious treatment for T2DM.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Uracila
/
Benzoatos
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Inibidores da Dipeptidil Peptidase IV
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Hipoglicemiantes
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article