کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1361018 981456 2008 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
N-1H-Benzimidazol-5-ylbenzenesulfonamide derivatives as potent hPXR agonists
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
N-1H-Benzimidazol-5-ylbenzenesulfonamide derivatives as potent hPXR agonists
چکیده انگلیسی

The Human Pregnane X Receptor (hPXR) is a nuclear receptor that regulates the expression of phase I and phase II drug-metabolizing enzymes, as well as that of drug transporters. Because this receptor plays a critical role in protecting tissues from potentially toxic endo- and xenobiotics, highly active agonists could represent novel therapeutic tools in treating several human diseases. Using an in vitro screening reporter system that allow to characterize hPXR activators and a first step of chemical modifications of an original agonist ligand (C2BA-4, 1-(2-chlorophenyl)-N-[1-(1-phenylethyl)-1H-benzimidazol-5-yl]methanesulfonamide), we identified compounds with a N-1H-benzimidazol-5-ylbenzenesulfonamide scaffold as a potent family of hPXR agonists. Further chemical modifications allowed us to identify enhanced activators, notably N-(1-benzyl-1H-benzimidazol-5-yl)-2,3,4,5,6-pentamethylbenzenesulfonamide (6n) with an EC50 value in the subnanomolar range. Accordingly to their potent EC50, these compounds induced an efficient protection of hPXR against proteolytic digestion by trypsin even at very low ligand concentrations and were able to induce the expression of the main target genes of hPXR, CYP3A4 and CYP2B6, in primary cultures of human hepatocytes.

In this study, we identified compound 6n as a potent agonist of hPXR with active concentration in the subnanomolar range.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 16, Issue 7, 1 April 2008, Pages 3537–3549
نویسندگان
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