Journal of medicinal chemistry, 2005-10, Vol.48 (21), p.6696-6712
2005
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Details
- Autor(en) / Beteiligte
- Titel
- Perhydroquinolylbenzamides as novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
- Ist Teil von
- Journal of medicinal chemistry, 2005-10, Vol.48 (21), p.6696-6712
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2005
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- High-throughput screening identified 5 as a weak inhibitor of 11beta-HSD1. Optimization of the structure led to a series of perhydroquinolylbenzamides, some with low nanomolar inhibitory potency. A tertiary benzamide is required for biological activity and substitution of the terminal benzamide with either electron-donating or -withdrawing groups is tolerated. The majority of the compounds show selectivity of >20 to >700-fold over 11beta-HSD2. Analogues which showed >50% inhibition of 11beta-HSD1 at 1 muM in an cellular assay were screened in an ADX mouse model. A maximal response of >70% reduction of liver corticosterone levels was observed for three compounds; 9m, 25 and 49.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-2623eISSN: 1520-4804Titel-ID: cdi_proquest_miscellaneous_68682506
- Format
- –
- Schlagworte
- 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors, Adrenalectomy, Animals, Benzamides - chemical synthesis, Benzamides - chemistry, Benzamides - pharmacology, Cells, Cultured, Corticosterone - metabolism, Hepatocytes - drug effects, Hepatocytes - metabolism, Humans, Hydroquinones - chemical synthesis, Hydroquinones - chemistry, Hydroquinones - pharmacology, Liver - drug effects, Liver - metabolism, Male, Mice, Rats, Rats, Sprague-Dawley, Stereoisomerism, Structure-Activity Relationship