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.
Department of Ophthalmology , Columbia University Medical Center , New York , New York 10032 , United States.
J Med Chem. 2019 Jun 13;62(11):5470-5500. doi: 10.1021/acs.jmedchem.9b00352. Epub 2019 May 28.
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.
视黄醇结合蛋白 4（RBP4）作为血液中全反式视黄醇（1）的转运蛋白，它被认为是一种脂肪因子。该蛋白的血浆水平升高与糖尿病、肥胖、心血管疾病和非酒精性脂肪性肝病（NAFLD）有关。最近有报道称，脂肪细胞特异性过表达 RBP4 可导致小鼠肝脂肪变性。我们之前鉴定出一种口服生物可利用的 RBP4 拮抗剂，它可显著降低 Abca4 基因敲除小鼠的血清 RBP4 水平，同时使补体系统蛋白表达正常化，并减少视网膜色素上皮中二视黄醇的形成。本文描述了新型 RBP4 拮抗剂 48 和 59 的发现，它们在急性口服给药后可使小鼠的血清 RBP4 水平降低超过 80%。此外，59 在转基因 adi-hRBP4 小鼠肝脂肪变性模型中显示出疗效，这表明 RBP4 拮抗剂也可能对治疗 NAFLD 具有治疗作用。
