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

Franck Lepifre; Serge Christmann-Franck; Didier Roche; Caroline Leriche; Denis Carniato; Christine Charon; Sophie Bozec; Liliane Doare; Fabien Schmidlin; Marc Lecomte; Eric Valeur

doi:10.1016/j.bmcl.2009.02.123

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

Bioorg Med Chem Lett. 2009 Jul 1;19(13):3682-5. doi: 10.1016/j.bmcl.2009.02.123. Epub 2009 Mar 5.

Authors

Franck Lepifre¹, Serge Christmann-Franck, Didier Roche, Caroline Leriche, Denis Carniato, Christine Charon, Sophie Bozec, Liliane Doare, Fabien Schmidlin, Marc Lecomte, Eric Valeur

Affiliation

¹ Merck-Serono, 4 Avenue du Président Mitterrand, 91380 Chilly-Mazarin, France.

PMID: 19450980
DOI: 10.1016/j.bmcl.2009.02.123

Abstract

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).

MeSH terms

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

Substances

Amides
Enzyme Inhibitors
Spiro Compounds
11-beta-Hydroxysteroid Dehydrogenase Type 1