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 (BEI of 32.7) which was selective against human 11beta-HSD2 (selectivity ratio>200000).
Lepifre
Franck
F
Merck-Serono, 4 Avenue du Président Mitterrand, 91380 Chilly-Mazarin, France.
Christmann-Franck
Serge
S
Roche
Didier
D
Leriche
Caroline
C
Carniato
Denis
D
Charon
Christine
C
Bozec
Sophie
S
Doare
Liliane
L
Schmidlin
Fabien
F
Lecomte
Marc
M
Valeur
Eric
E
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D004791:Enzyme Inhibitors; D013141:Spiro Compounds; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1