Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection.
Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection.
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DOI：
10.1021/jm300171v
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发表时间：
2012-07-12
影响因子：
7.3
通讯作者：
Chang, Jinhong
中科院分区：
文献类型：
--
作者：
Yu, Wenquan;Gill, Tina;Wang, Lijuan;Du, Yanming;Ye, Hong;Qu, Xiaowang;Guo, Ju-Tao;Cuconati, Andrea;Zhao, Kang;Block, Timothy M.;Xu, Xiaodong;Chang, Jinhong
我们最近发现了含氧的N-烷基脱氧野尻霉素（DNJ）衍生物7（CM-10-18），在体外和体内都具有抗登革病毒（DENV）感染的抗病毒活性。这种亚氨基糖是有前途的，但在BHK细胞中对DENV的EC 50为6.5 μM，这限制了其在体内的使用。化合物7提出了活性关系分析的结构机会，我们在这里利用和报告。这些结构-活性关系研究导致类似物2 h、2l、3 j、3l、3v和4 b-4c具有针对DENV感染的纳摩尔抗病毒活性（EC 50 = 0.3-0.5 μM），同时保持低细胞毒性（CC 50> 500 μM，SI > 1000）。在雄性Sprague-Dawley大鼠中，化合物31在高达200 mg/kg的剂量下耐受良好，并显示出期望的PK特征，具有显著改善的生物利用度（F = 92 ± 4%）。
We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10-18) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising, but had an EC50 against DENV in BHK cells of 6.5 μM, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure-activity relationship studies led to analogs 2h, 2l, 3j, 3l, 3v and 4b–4c with nanomolar antiviral activity (EC50 = 0.3–0.5 μM) against DENV infection, while maintaining low cytotoxicity (CC50 > 500 μM, SI > 1000). In male Sprague-Dawley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).
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7.6
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