Fine-tuning the selectivity of aldosterone synthase inhibitors: structure-activity and structure-selectivity insights from studies of heteroaryl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one derivatives
| Autor: | Simon Lucas, Rolf W. Hartmann, Matthias Negri, Christina Zimmer, Ralf Heim |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Aldosterone synthase
Male Models Molecular Stereochemistry Protein Conformation Substrate Specificity Structure-Activity Relationship Protein structure Drug Discovery medicine Structure–activity relationship Moiety Animals Cytochrome P-450 CYP11B2 Humans Enzyme Inhibitors Rats Wistar biology Chemistry CYP1A2 medicine.disease Hyperaldosteronism Rats Fadrozole Drug Design biology.protein Quinolines Molecular Medicine Selectivity medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 54(7) |
| ISSN: | 1520-4804 |
| Popis: | Pyridine substituted 3,4-dihydro-1H-quinolin-2-ones (e.g., 1-3) constitute a class of highly potent and selective inhibitors of aldosterone synthase (CYP11B2), a promising target for the treatment of hyperaldosteronism, congestive heart failure, and myocardial fibrosis. Among these, ethyl-substituted 3 possesses high selectivity against CYP1A2. Rigidification of 3 by incorporation of the ethyl group into a 5- or 6-membered ring affords compounds with a pyrroloquinolinone or pyridoquinolinone molecular scaffold (e.g., 4 and 5). It was found that these molecules are even more potent and selective CYP11B2 inhibitors than their corresponding open-chain analogues. Moreover, pyrroloquinolinone 4 exhibits no inhibition of the six most important hepatic CYP enzymes as well as a bioavailability in the range of the marketed drug fadrozole. The SAR studies disclose that subtle changes in the heterocyclic moiety are responsible for either a strong or a weak inhibition of the highly homologous 11β-hydroxylase (CYP11B1). These results are not only important for fine-tuning the selectivity of CYP11B2 inhibitors but also for the development of selective CYP11B1 inhibitors that are of interest for the treatment of Cushing's syndrome and metabolic syndrome. |
| Databáze: | OpenAIRE |
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