Your browser doesn't support javascript.
loading
Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis.
Cioffi, Christopher L; Racz, Boglarka; Varadi, Andras; Freeman, Emily E; Conlon, Michael P; Chen, Ping; Zhu, Lei; Kitchen, Douglas B; Barnes, Keith D; Martin, William H; Pearson, Paul G; Johnson, Graham; Blaner, William S; Petrukhin, Konstantin.
Afiliación
  • Cioffi CL; Departments of Basic and Clinical Sciences and Pharmaceutical Sciences , Albany College of Pharmacy and Health Sciences , 106 New Scotland Avenue , Albany , New York 12208 , United States.
  • Racz B; Department of Ophthalmology , Columbia University Medical Center , New York , New York 10032 , United States.
  • Varadi A; Department of Ophthalmology , Columbia University Medical Center , New York , New York 10032 , United States.
  • Martin WH; WHM Consulting LLC , 111 Sterling City Road , Lyme , Connecticut 06371 , United States.
  • Pearson PG; Pearson Pharma Partners , 31194 La Baya Drive , Westlake Village , California 91361 , United States.
  • Johnson G; NuPharmAdvise LLC , 3 Lakeside Drive , Sanbornton , New Hampshire 03269 , United States.
  • Blaner WS; Department of Medicine , Columbia University Medical Center , New York , New York 10032 , United States.
  • Petrukhin K; Department of Ophthalmology , Columbia University Medical Center , New York , New York 10032 , United States.
J Med Chem ; 62(11): 5470-5500, 2019 06 13.
Article en En | MEDLINE | ID: mdl-31079449
Retinol-binding protein 4 (RBP4) serves as a transporter for all- trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked to diabetes, obesity, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Recently, adipocyte-specific overexpression of RBP4 was reported to cause hepatic steatosis in mice. We previously identified an orally bioavailable RBP4 antagonist that significantly lowered RBP4 serum levels in Abca4-/- knockout mice with concomitant normalization of complement system protein expression and reduction of bisretinoid formation within the retinal pigment epithelium. We describe herein the discovery of novel RBP4 antagonists 48 and 59, which reduce serum RBP4 levels by >80% in mice upon acute oral dosing. Furthermore, 59 demonstrated efficacy in the transgenic adi-hRBP4 murine model of hepatic steatosis, suggesting that RBP4 antagonists may also have therapeutic utility for the treatment of NAFLD.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidinas / Diseño de Fármacos / Proteínas Plasmáticas de Unión al Retinol / Hígado Graso Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidinas / Diseño de Fármacos / Proteínas Plasmáticas de Unión al Retinol / Hígado Graso Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos