کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1368619 981704 2016 5 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation
چکیده انگلیسی

Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 26, Issue 9, 1 May 2016, Pages 2339–2343
نویسندگان
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