RESUMO
The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.
Assuntos
Acetatos/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Fígado/enzimologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Tetrazóis/síntese química , Acetatos/química , Acetatos/farmacologia , Animais , Linhagem Celular , Difusão , Cães , Feminino , Glândula de Harder/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Técnicas In Vitro , Transportador 1 de Ânion Orgânico Específico do Fígado , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ratos , Ratos Sprague-Dawley , Pele/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Especificidade da Espécie , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologia , Distribuição TecidualRESUMO
SCD1 inhibition may represent a novel treatment for obesity, type-2 diabetes and related metabolic disorders. A prototype thiazole amide analog 13 (MF-152) was identified as an excellent tool in the study of SCD biology in animals.