کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5554751 1558885 2017 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
A novel aldosterone synthase inhibitor ameliorates mortality in pressure-overload mice with heart failure
ترجمه فارسی عنوان
یک مهارکننده سنتاز آلدوسترون جدید، باعث کاهش مرگ و میر در موشهای پربار فشار با نارسایی قلبی می شود
کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب سلولی و مولکولی
چکیده انگلیسی

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmacology - Volume 795, 15 January 2017, Pages 58-65
نویسندگان
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