Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy.
J Enzyme Inhib Med Chem
; 35(1): 152-164, 2020 Dec.
Article
em En
| MEDLINE
| ID: mdl-31742469
ABSTRACT
Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibitory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity. Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and 34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide-streptozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular architectures and antihyperglycaemic activity could be developed in the treatment of T2D.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Terpenos
/
Desenho de Fármacos
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Diabetes Mellitus Tipo 2
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Inibidores Enzimáticos
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Proteína Tirosina Fosfatase não Receptora Tipo 1
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Hipoglicemiantes
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Enzyme Inhib Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China