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 IC(50) of 2.5 microM. Compound 10 provided a useful scaffold to initiate a medicinal chemistry campaign.
McMasters
Daniel R
DR
Department of Chemistry Modeling & Informatics, Merck & Co, Inc, NJ 07065, United States. daniel_mcmasters@merck.com
Garcia-Calvo
Margarita
M
Maiorov
Vladimir
V
McCann
Margaret E
ME
Meurer
Roger D
RD
Bull
Herbert G
HG
Lisnock
Jeanmarie
J
Howell
Kobporn L
KL
Devita
Robert J
RJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry* / Q000494:pharmacology; D006224:Cricetinae; D004285:Dogs; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry* / Q000494:pharmacology; D008253:Macaca mulatta; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008956:Models, Chemical; D008968:Molecular Conformation; D051381:Rats; D012984:Software; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013552:Swine
D000924:Anticholesteremic Agents; D048289:Imidazolidines; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D013141:Spiro Compounds