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

• Published in: Bioorganic & medicinal chemistry letters 2009-06, Vol.19 (11), p.2965-2968
• Main Authors: McMasters, Daniel R., Garcia-Calvo, Margarita, Maiorov, Vladimir, McCann, Margaret E., Meurer, Roger D., Bull, Herbert G., Lisnock, JeanMarie, Howell, Kobporn L., DeVita, Robert J.
• Format: Article
• Language: English
• Subjects: Animals; Anticholesteremic Agents - chemistry; Anticholesteremic Agents - pharmacology; Biological and medical sciences; Cholesterol absorption inhibitors; Cricetinae; Dogs; Drug Design; General and cellular metabolism. Vitamins; Guinea Pigs; Humans; Imidazolidines - chemistry; Imidazolidines - pharmacology; Macaca mulatta; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Models, Chemical; Molecular Conformation; Molecular modeling; NPC1L1 inhibitors; Pharmacology. Drug treatments; Rats; Software; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Superposition; Swine; Virtual screening
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.04.031

A series of spiroimidazolidinone NPC1L1 inhibitors was discovered by virtual screening of the Merck corporate sample repository using 3D-similarity-based 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 2.5μM. Compound 10 provided a useful scaffold to initiate a medicinal chemistry campaign.