Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11β-hydroxysteroid dehydrogenase type I
2012
Valeur, Eric | Christmann-Franck, Serge | Lepifre, Franck | Carniato, Denis | Cravo, Daniel | Charon, Christine | Bozec, Sophie | Musil, Djordje | Hillertz, Per | Doare, Liliane | Schmidlin, Fabien | Lecomte, Marc | Schultz, Melanie | Roche, Didier
Indole-pyrrolidines were identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) by high-throughput screening. Optimisation of the initial hit through structure-based design led to 7-azaindole-derivatives, with the best analogues displaying single digit nanomolar IC₅₀ potency. The modeling hypotheses were confirmed by solving the X-ray co-crystal structure of one of the lead compounds. These compounds were selective against 11β-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11β-HSD1 (IC₅₀<1μM) in a cellular model (3T3L1 adipocytes)
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