کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10583710 | 981298 | 2014 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Design and discovery of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide inhibitors of HIV-1 integrase
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کلمات کلیدی
CPEElvitegravirDMADINSTIsDimethylacetylenedicarboxylateLEDGF/p75 - LEDGF / p75Cytopathic effect - اثر سیتوپاتیکELV - اصلIntegrase - انتگرالRAL - رالRaltegravir - رالتانگاریویرPharmacodynamics - فارماکودینامیکPharmacokinetics - فارماکوکینتیکlens epithelium-derived growth factor - فاکتور رشد مشتق از اپیتلیوم لنزHIV-1 integrase inhibitors - مهار کننده های انتگرال HIV-1
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Raltegravir (RAL) is a first clinically approved integrase (IN) inhibitor for the treatment of HIV but rapid mutation of the virus has led to chemo-resistant strains. Therefore, there is a medical need to develop new IN inhibitors to overcome drug resistance. At present, several IN inhibitors are in different phases of clinical trials and few have been discontinued due to toxicity and lack of efficacy. The development of potent second-generation IN inhibitors with improved safety profiles is key for selecting new clinical candidates. In this article, we report the design and synthesis of potent 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide analogues as second-generation IN inhibitors. These compounds satisfy two structural requirements known for potent inhibition of HIV-1 IN catalysis: a metal chelating moiety and a hydrophobic functionality necessary for selectivity against the strand transfer reaction. Most of the new compounds described herein are potent and selective for the strand transfer reaction and show antiviral activity in cell-based assays. Furthermore, this class of compounds are drug-like and suitable for further optimization and preclinical studies.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 22, Issue 19, 1 October 2014, Pages 5446-5453
Journal: Bioorganic & Medicinal Chemistry - Volume 22, Issue 19, 1 October 2014, Pages 5446-5453
نویسندگان
Daoguang Zhang, Bikash Debnath, Shenghui Yu, Tino Wilson Sanchez, Frauke Christ, Yang Liu, Zeger Debyser, Nouri Neamati, Guisen Zhao,