Pharmacological and structure-activity relationship studies of oleoyl-lysophosphatidylinositol synthetic mimetics.
Pharmacol Res
; 172: 105822, 2021 10.
Article
em En
| MEDLINE
| ID: mdl-34411732
ABSTRACT
Metabolic diseases, such as obesity and type 2 diabetes, are relentlessly spreading worldwide. The beginning of the 21st century has seen the introduction of mechanistically novel types of drugs, aimed primarily at keeping these pathologies under control. In particular, an important family of therapeutics exploits the beneficial physiology of the gut-derived glucagon-like peptide-1 (GLP-1), with important clinical benefits, from glycaemic control to cardioprotection. Nonetheless, these protein-based drugs act systemically as exogenous GLP-1 mimetics and are not exempt from side effects. The food-derived lipid oleoyl-lysophosphatidylinositol (LPI) is a potent GPR119-dependent GLP-1 secreting agent. Here we present a structure-activity relationship (SAR) study of a synthetic library of oleoyl-LPI mimetics capable to induce the physiological release of GLP-1 from gastrointestinal enteroendocrine cells (EECs). The best lead compounds have shown potent and efficient release of GLP-1 in vitro from human and murine cells, and in vivo in diabetic db/db mice. We have also generated a molecular model of oleoyl-LPI, as well as its best performing analogues, interacting with the orthosteric site of GPR119, laying foundational evidence for their pharmacological activity.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Lisofosfolipídeos
/
Células Enteroendócrinas
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Diabetes Mellitus Experimental
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Peptídeo 1 Semelhante ao Glucagon
Limite:
Animals
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Humans
Idioma:
En
Revista:
Pharmacol Res
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Austrália
País de publicação:
HOLANDA
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HOLLAND
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NETHERLANDS
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NL
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PAISES BAJOS
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THE NETHERLANDS