Fine-Tuning the Selectivity of Aldosterone Synthase Inhibitors: Structure鈭扐ctivity and Structure鈭扴electivity Insights from Studies of Heteroaryl Substituted 1,2,5,6-Tetrahydropyrrolo[3,2,1-ij]q

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• 作者：Simon Lucas ; Matthias Negri ; Ralf Heim ; Christina Zimmer ; Rolf W. Hartmann
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2307-2319
• 全文大小：1088K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

Pyridine substituted 3,4-dihydro-1H-quinolin-2-ones (e.g., 1鈭?b>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 11尾-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鈥檚 syndrome and metabolic syndrome.