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1.
Bioorg Med Chem ; 27(11): 2220-2227, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31029550

RESUMO

Antagonizing transcriptional activity of farnesoid X receptor (FXR) in the intestine has been reported as an effective means for the treatment of nonalcoholic fatty liver disease, type 2 diabetes and obesity. We describe herein that the building blocks necessary to maintain the antagonism of our chemotype were investigated in order to modulate in vivo pharmacokinetic behavior and the tissue distribution without blunting the activity against FXR. A comprehensive understanding of the structure-activity relationship led to analog 30, which is superior to 12 in terms of its pharmacokinetic profiles by oral administration and its tissue distribution toward target tissues (liver and ileum) in rats while preserving the in vitro activity of 12 against FXR. Thus, 30 should be a candidate compound to investigate the effects of inhibiting FXR activity while simultaneously improving the outcome of nonalcoholic fatty liver disease, type 2 diabetes and obesity.


Assuntos
Benzimidazóis/farmacocinética , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Administração Intravenosa , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/síntese química , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Íleo/metabolismo , Fígado/metabolismo , Masculino , Estrutura Molecular , Ratos Sprague-Dawley , Relação Estrutura-Atividade
2.
ACS Med Chem Lett ; 9(2): 78-83, 2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29456791

RESUMO

Farnesoid X receptor (FXR) plays a major role in the control of cholesterol metabolism. Antagonizing transcriptional activity of FXR is an effective means to treat the relevant metabolic syndrome. Some of antagonists so far have the charged functions; however, they may negatively affect the pharmacokinetics. We describe herein a structure-activity relationship (SAR) exploration of nonacidic FXR antagonist 6 focusing on two regions in the structure and biological evaluation of nonacidic 10 with the characteristic N-acylated piperidine group obtained from SAR studies. As the robust affinity to FXR is feasible with our nonacidic analogue, 10 is among the most promising candidates for in vivo testing.

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