Exploiting the Chromone Scaffold for the Development of Inhibitors of Corticosteroid Biosynthesis
| Autor: | Alessandra Bisi, Rolf W. Hartmann, Federica Belluti, Angela Rampa, Matthias Engel, Qingzhong Hu, Silvia Gobbi, Christina Zimmer |
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| Přispěvatelé: | Gobbi, Silvia, Hu, Qingzhong, Zimmer, Christina, Engel, Matthia, Belluti, Federica, Rampa, Angela, Hartmann, Rolf W., Bisi, Alessandra |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Scaffold Cell Survival Pyridines Heme iron 01 natural sciences Substrate Specificity Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Biosynthesis Adrenal Cortex Hormones Heterocyclic Compounds Drug Discovery Moiety Animals Cytochrome P-450 CYP11B2 Cytochrome P-450 Enzyme Inhibitors Humans Chromone chemistry.chemical_classification Aromatase Inhibitors Cytochrome inhibitors Steroid 17-alpha-Hydroxylase Combinatorial chemistry 0104 chemical sciences Rats CYP11B2 Molecular Docking Simulation CYP11B1 010404 medicinal & biomolecular chemistry 030104 developmental biology Enzyme chemistry Chromones Drug Design Molecular Medicine Steroid 11-beta-Hydroxylase |
| Zdroj: | Journal of medicinal chemistry. 59(6) |
| ISSN: | 1520-4804 |
| Popis: | The inhibition of corticosteroid biosynthesis could be considered as an emerging strategy to reduce their abnormally high levels, and in this framework CYP11B1 and CYP11B2 represent the most promising targets. In continuing our studies on flavonoid-like scaffolds as privileged structures in medicinal chemistry, in this paper we describe a small library of pyridyl- and imidazolylmethylchromones as potential inhibitors of these enzymes. Testing results proved that position 3 of the chromone scaffold is the most favorable for the introduction of the heme-coordinating heterocycles and, among them, the 4-imidazolyl moiety is the most convenient for the interaction with the heme iron of the selected cytochromes. A low nanomolar inhibitor of CYP11B1 (5c) was obtained, endowed with reasonable selectivity toward CYP11B2 and able to better discriminate with respect to CYP17 and CYP19. |
| Databáze: | OpenAIRE |
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