Discovery and structure-activity relationships of pentanedioic acid diamides as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type I.
Benzylamides of pentanedioic acid were identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) by high-throughput screening. Optimisation to 2-adamantyl amides yielded inhibitors with single digit nanomolar IC(50)s on the 11beta-HSD1 human isoform. The hydroxy adamantyl amide lead compound was selective against 11beta-hydroxysteroid dehydrogenase type 2 (selectivity ratio >1000) and displayed good inhibition of 11beta-HSD1 (IC(50)<0.1microM) in a cellular model (3T3L1 adipocytes).
Roche
Didier
D
Merck-Serono, Chilly-Mazarin, France.
Carniato
Denis
D
Leriche
Caroline
C
Lepifre
Franck
F
Christmann-Franck
Serge
S
Graedler
Ulrich
U
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; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D041721:3T3-L1 Cells; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2