A novel aldosterone synthase inhibitor ameliorates mortality in pressure-overload mice with heart failure

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• 作者：Shinji Furuzono^a ; ^b ; ^{furuzono.shinji.k5@daiichisankyo.co.jp} ; Masaki Meguro^c ; Satoru Miyauchi^d ; Shinichi Inoue^e ; Tsuyoshi Homma^a ; Keisuke Yamada^f ; Yoh-ichi Tagawa^b ; Futoshi Nara^c ; Takahiro Nagayama^g
• 关键词：Aldosterone synthase ; Heart failure ; Transverse aortic constriction
• 刊名：European Journal of Pharmacology
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：795
• 期：Complete
• 页码：58-65
• 全文大小：1495 K
• 卷排序：795

文摘

It has been elucidated that mineralocorticoid receptor antagonists reduce mortality in patients with congestive heart failure and post-acute myocardial infarction. A direct inhibition of aldosterone synthase (CYP11B2) is also expected to have therapeutic benefits equal in quality to mineralocorticoid receptor antagonists in terms of reducing mineralocorticoid receptor signaling. Therefore, we have screened our chemical libraries and identified a novel and potent aldosterone synthase inhibitor, 2,2,2-trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-y}-1-[1-(methylsulfonyl)piperidin-4-yl]ethanol (compound 1), by lead optimization. Pharmacological properties of compound 1 were examined in in vitro cell-based assays and an in vivo mouse model of pressure-overload hypertrophy by transverse aortic constriction (TAC). Compound 1 showed potent CYP11B2 inhibition against human and mouse enzymes (IC50; 0.003 μM and 0.096 μM, respectively) in a cell-based assay. The oral administration of 0.06% compound 1 in the food mixture of a mouse TAC model significantly reduced the plasma aldosterone level and ameliorated mortality rate. This study is the first to demonstrate that a CYP11B2 inhibitor improved survival rates of heart failure induced by pressure-overload in mice. The treatment of 0.06% compound 1 did not elevate plasma potassium level in this model, although further evaluation of hyperkalemia is needed. These results suggest that compound 1 can be developed as a promising oral CYP11B2 inhibitor for pharmaceutical applications. Compound 1 could also be a useful compound for clarifying the role of aldosterone in cardiac hypertrophy.