1004774-99-5Relevant articles and documents
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
, p. 5470 - 5500 (2019)
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.
AZABENZIMIDAZOLYL COMPOUNDS
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Page/Page column 68, (2008/06/13)
Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I), as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
