Spiroimidazolidinone NPC1L1 inhibitors. 1: Discovery by 3D-similarity-based virtual screening

A series of spiroimidazolidinone NPC1L1 inhibitors was discovered by virtual screening of the Merck corporate sample repository using 3D-similarity-based screening. Selection of 330 compounds for testing in an in vitro NPC1L1 binding assay yielded six hits in six distinct chemical series. Follow-up 2D similarity searching yielded several sub- to low-micromolar leads; among these was spiroimidazolidinone 10, with an IC50 of 2.5 μM. Compound 10 provided a useful scaffold to initiate a medicinal chemistry campaign.

Graphical abstractA series of spiroimidazolidinone NPC1L1 inhibitors was discovered by virtual screening of the Merck corporate sample repository using 3D-similarity-based screening.Figure optionsDownload full-size imageDownload as PowerPoint slide