SCH 48461

SCH-48461 is a cholesterol absorption inhibitor.

During the early phases of an NPC1L1 inhibitor discovery program at Schering-Plough, conformationally restricted analogs based on the 2-azetidinone backbone were targeted by Burnett and co-workers. Early in the biological evaluation, it became apparent that even though the in vitro ACAT inhibitory activity of these analogs was modest (e.g., IC₅₀ values of 2–50 mM), they exhibited significant activity in a cholesterol-fed hamster model (CFH). The discovery of the prototypical 2-azetidinone CAI, SCH-48461 (ACAT IC₅₀ ~26 mM, ED₅₀ of CE reduction in hamsters ~2.2 mpk) and the details of the first-generation SAR have been described in detail.