Discovery of phenylpyrrolidine derivatives as a novel class of retinol binding protein 4 (RBP4) reducers.

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.