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.
MeSH terms
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Animals
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Anticholesteremic Agents / chemistry*
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Anticholesteremic Agents / pharmacology
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Cricetinae
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Dogs
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Drug Design
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Guinea Pigs
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Humans
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Imidazolidines / chemistry*
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Imidazolidines / pharmacology
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Macaca mulatta
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / metabolism
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Membrane Transport Proteins
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Models, Chemical
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Molecular Conformation
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Rats
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Software
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Spiro Compounds / chemistry*
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Spiro Compounds / pharmacology
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Swine
Substances
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Anticholesteremic Agents
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Imidazolidines
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Membrane Proteins
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Membrane Transport Proteins
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NPC1L1 protein, human
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Spiro Compounds