Discovery and structure-guided drug design of inhibitors of 11beta-hydroxysteroid-dehydrogenase type I based on a spiro-carboxamide scaffold

Spiro-carboxamides were identified as inhibitors of 11beta-hydroxysteroid-dehydrogenase type 1 by high-throughput screening. Structure-based drug design was used to optimise the initial hit yielding a sub-nanomolar IC(50) inhibitor (0.5nM) on human 11beta-HSD1 with a high binding efficiency index (B...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-07, Vol.19 (13), p.3682-3685
Hauptverfasser:	Lepifre, Franck, Christmann-Franck, Serge, Roche, Didier, Leriche, Caroline, Carniato, Denis, Charon, Christine, Bozec, Sophie, Doare, Liliane, Schmidlin, Fabien, Lecomte, Marc, Valeur, Eric
Format:	Artikel
Sprache:	eng
Schlagworte:	11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism Amides - chemistry Amides - pharmacology Binding Sites Computer Simulation Drug Design Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Spiro Compounds - chemistry Spiro Compounds - pharmacology Structure-Activity Relationship
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Zusammenfassung:	Spiro-carboxamides were identified as inhibitors of 11beta-hydroxysteroid-dehydrogenase type 1 by high-throughput screening. Structure-based drug design was used to optimise the initial hit yielding a sub-nanomolar IC(50) inhibitor (0.5nM) on human 11beta-HSD1 with a high binding efficiency index (BEI of 32.7) which was selective against human 11beta-HSD2 (selectivity ratio>200000).
ISSN:	1464-3405
DOI:	10.1016/j.bmcl.2009.02.123