| Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs. | |
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MedLine Citation:
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PMID: 19660947 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In the late 1980's reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H(1) binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H(1) assays. |
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Authors:
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Robert Aslanian; John J Piwinski; Xiaohong Zhu; Tony Priestley; Steve Sorota; Xiao-Yi Du; Xue-Song Zhang; Robbie L McLeod; Robert E West; Shirley M Williams; John A Hey |
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Publication Detail:
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Type: Journal Article Date: 2009-08-05 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: 19 ISSN: 1464-3405 ISO Abbreviation: Bioorg. Med. Chem. Lett. Publication Date: 2009 Sep |
Date Detail:
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Created Date: 2009-08-17 Completed Date: 2009-11-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9107377 Medline TA: Bioorg Med Chem Lett Country: England |
Other Details:
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Languages: eng Pagination: 5043-7 Citation Subset: IM |
Affiliation:
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The Schering Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA. robert.aslanian@spcorp.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Electrocardiography Guinea Pigs Histamine H1 Antagonists, Non-Sedating / chemical synthesis, chemistry*, pharmacology Humans Protein Binding Receptors, Histamine H1 / metabolism* Structure-Activity Relationship Terfenadine / analogs & derivatives*, chemistry, pharmacology Trans-Activators / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/ERG protein, human; 0/Histamine H1 Antagonists, Non-Sedating; 0/Receptors, Histamine H1; 0/Trans-Activators; 50679-08-8/Terfenadine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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