Identification of an oxime-containing C-glucosylarene as a potential inhibitor of sodium-dependent glucose co-transporter 2.
Eur J Med Chem
; 143: 611-620, 2018 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-29216560
ABSTRACT
Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C-N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC50 > 50 µM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 µM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oximas
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Diabetes Mellitus Experimental
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Inibidores do Transportador 2 de Sódio-Glicose
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Hipoglicemiantes
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Monossacarídeos
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2018
Tipo de documento:
Article