Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11[beta]-hydroxysteroid dehydrogenase type I
Indole-pyrrolidines were identified as inhibitors of 11[beta]-hydroxysteroid dehydrogenase type 1 (11[beta]-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 IC5...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-09, Vol.22 (18), p.5909-5914 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | 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 |
| description | Indole-pyrrolidines were identified as inhibitors of 11[beta]-hydroxysteroid dehydrogenase type 1 (11[beta]-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 11[beta]-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11[beta]-HSD1 (IC50 < 1 AmM) in a cellular model (3T3L1 adipocytes) |
| doi_str_mv | 10.1016/j.bmcl.2012.07.070 |
| format | Article |
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| ispartof | Bioorganic & medicinal chemistry letters, 2012-09, Vol.22 (18), p.5909-5914 |
| issn | 0960-894X |
| language | eng |
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| source | Elsevier ScienceDirect Journals |
| subjects | Indexing in process |
| title | Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11[beta]-hydroxysteroid dehydrogenase type I |
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