Retinol-binding protein 4 (RBP4) serves as a transporter for all-trans-retinol in the blood that has also been proposed to act as an adipokine. Elevated RBP4 plasma levels have been linked to multiple metabolic disorders that include diabetes, obesity, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD). Importantly, adipocyte-specific overexpression of RBP4 was reported to cause hepatic steatosis in mice. We previously identified orally bioavailable RBP4 antagonists that significantly lowered RBP4 serum levels in the Abca4−/− knockout mouse with concomitant normalization of complement system protein expression and reduction of bisretinoid formation within the retina. This lecture will highlight additional work conducted as part of the NIH Blueprint Neurotherapeutics Network whereby novel RBP4 antagonists with excellent in vitro RBP4 binding affinity and favorable drug-like characteristics that reduce serum RBP4 levels in a robust manner (&gt;80%) in mice upon acute oral dosing. Furthermore, these compounds 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.

Design, synthesis, and preclinical efficacy of novel nonretinoid antagonists of retinol-binding protein 4 in the mouse model of hepatic steatosis

ACS Spring Meeting 2021

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