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

  • Bioorg Med Chem Lett. 2009 Jun 1;19(11):2965-8. doi: 10.1016/j.bmcl.2009.04.031.
Daniel R McMasters  1 ,  Margarita Garcia-Calvo ,  Vladimir Maiorov ,  Margaret E McCann ,  Roger D Meurer ,  Herbert G Bull ,  Jeanmarie Lisnock ,  Kobporn L Howell ,  Robert J Devita
Affiliations
  • 1. Department of Chemistry Modeling & Informatics, Merck & Co, Inc, NJ 07065, United States. [email protected]
PMID: 19410454 DOI: 10.1016/j.bmcl.2009.04.031
Abstract

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.