Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis.
Christopher L CioffiBoglarka RaczAndras VaradiEmily E FreemanMichael P ConlonPing ChenLei ZhuDouglas B KitchenKeith D BarnesWilliam H MartinPaul G PearsonGraham JohnsonWilliam S BlanerKonstantin PetrukhinPublished in: Journal of medicinal chemistry (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.
Keyphrases
- binding protein
- high fat diet induced
- cardiovascular disease
- mouse model
- type diabetes
- insulin resistance
- adipose tissue
- small molecule
- weight loss
- cell proliferation
- high throughput
- stem cells
- weight gain
- drug induced
- cardiovascular events
- body mass index
- bone marrow
- hepatitis b virus
- extracorporeal membrane oxygenation
- amino acid
- liver fibrosis
- wild type
- glycemic control