In vivo active aldosterone synthase inhibitors with improved selectivity: lead optimization providing a series of pyridine substituted 3,4-dihydro-1H-quinolin-2-one derivatives
| Autor: | Barbara Birk, Katarzyna E. Schewe, Ralf Heim, Rolf W. Hartmann, Simon Lucas, Christina Ries |
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| Rok vydání: | 2008 |
| Předmět: |
Aldosterone synthase
Stereochemistry Pyridines Chemistry Pharmaceutical Quinolones Chemical synthesis chemistry.chemical_compound Inhibitory Concentration 50 In vivo Cytochrome P-450 CYP1A2 Drug Discovery Tetralone Animals Cytochrome P-450 CYP11B2 Humans Isoquinoline Enzyme Inhibitors chemistry.chemical_classification biology Temperature U937 Cells Carbon Rats Enzyme chemistry Liver Enzyme inhibitor Drug Design biology.protein Molecular Medicine Bioisostere |
| Zdroj: | Journal of medicinal chemistry. 51(24) |
| ISSN: | 1520-4804 |
| Popis: | Pyridine substituted naphthalenes (e.g., I-III) constitute a class of potent inhibitors of aldosterone synthase (CYP11B2). To overcome the unwanted inhibition of the hepatic enzyme CYP1A2, we aimed at reducing the number of aromatic carbons of these molecules because aromaticity has previously been identified to correlate positively with CYP1A2 inhibition. As hypothesized, inhibitors with a tetrahydronaphthalene type molecular scaffold (1-11) exhibit a decreased CYP1A2 inhibition. However, tetralone 9 turned out to be cytotoxic to the human cell line U-937 at higher concentrations. Consequent structural optimization culminated in the discovery of heteroaryl substituted 3,4-dihydro-1H-quinolin-2-ones (12-26), with 12, a bioisostere of 9, being nontoxic up to 200 microM. The investigated molecules are highly selective toward both CYP1A2 and a wide range of other cytochrome P450 enzymes and show a good pharmacokinetic profile in vivo (e.g., 12 with a peroral bioavailability of 71%). Furthermore, isoquinoline derivative 21 proved to significantly reduce plasma aldosterone levels of ACTH stimulated rats. |
| Databáze: | OpenAIRE |
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