Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Bioorg Med Chem. 2022 Jan 15;54:116553. doi: 10.1016/j.bmc.2021.116553. Epub 2021 Dec 12.
Retinol-binding protein 4 (RBP4) is a potential drug target for metabolic and ophthalmologic diseases. A high-throughput screening of our compound library has identified a small-molecule RBP4 reducer 7a, as a hit compound. Aiming to provide a suitable tool for investigating the pharmacological effects of RBP4 reducers, we conducted a structure-activity relationship study of 7a. Exploration of the aryl head, oxazole core, and propanoic acid tail of 7a resulted in the discovery of novel, potent, and orally available phenylpyrrolidine derivatives 43b and 43c. Compound 43b had a potent and long-lasting blood RBP4-level-reducing effect when orally administered to mice at a dose as low as 0.3 mg/kg.
视黄醇结合蛋白 4（RBP4）是代谢和眼科疾病的潜在药物靶点。我们对化合物文库进行了高通量筛选，发现了小分子 RBP4 还原剂 7a，这是一种有效化合物。为了提供一种合适的工具来研究 RBP4 还原剂的药理作用，我们对 7a 进行了构效关系研究。对 7a 的芳基头部、恶唑核心和丙酸尾部进行探索，发现了新型、有效且可口服的苯基吡咯烷衍生物 43b 和 43c。当以 0.3mg/kg 的低剂量口服给予小鼠时，化合物 43b 具有强大且持久的降低血液 RBP4 水平的作用。
