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J Med Chem:左建平等发现2,4-二氨基喹唑啉类登革病毒抑制剂

2012-07-17 上海药物所 上海药物所

登革病毒(Dengue Fever Virus,DV)感染引起的登革热、登革出血热/登革休克综合征已成为国际上重要的公共卫生问题,这种可致命性的病毒性传染病已威胁到全球1/3的人口。目前,世界上针对DV感染尚无有效疫苗可用于预防,也没有特效抗病毒药物可用于治疗。 左建平、胡有洪、南发俊和李佳课题组在早期欧盟项目的支持下,通过高通量筛选,从筛选中心分子库中发现的抑制登革病毒活性化合物开始进行成药性

登革病毒(Dengue Fever Virus,DV)感染引起的登革热、登革出血热/登革休克综合征已成为国际上重要的公共卫生问题,这种可致命性的病毒性传染病已威胁到全球1/3的人口。目前,世界上针对DV感染尚无有效疫苗可用于预防,也没有特效抗病毒药物可用于治疗。

左建平、胡有洪、南发俊和李佳课题组在早期欧盟项目的支持下,通过高通量筛选,从筛选中心分子库中发现的抑制登革病毒活性化合物开始进行成药性优化,深入的构效关系研究和结构优化,获得化合物YHHU-1157(图1)其抗DV活性优于已报道化合物,在DV 感染的C6/36等细胞株上显示了优良的抗DENV-2病毒活性,其EC50 为2.8 nM, 治疗指数高SI > 1000。

初步药代评价结果显示,成药性好,对hERG钾电流影响作用较弱(IC50=20.2 μM)。该类化合物与以往文献报道的活性化合物结构完全不同,拥有自主知识产权,对开展抗登革病毒药物的研究具有开创性意义。相关工作发表在:J. Med.Chem.,2012, 55(7), 3135-3143(该主要工作由晁博,董贤昆,唐炜完成)。

doi:10.1021/jm2015952
PMC:
PMID:

Discovery and Optimization of 2,4-Diaminoquinazoline Derivatives as a New Class of Potent Dengue Virus Inhibitors

Bo Chao†, Xian-Kun Tong†, Wei Tang†, De-Wen Li†, Pei-Lan He†, Jean-Michel Garcia‡, Li-Min Zeng†, An-Hui Gao†, Li Yang†, Jia Li†, Fa-Jun Nan†, Michael Jacobs§, Ralf Altmeyer‡, Jian-Ping Zuo*†, and You-Hong Hu*†

The results of a high-throughput screening assay using the DENV-2 replicon showed that the 2,4-diaminoquinazoline derivative 4a has a high dengue virus inhibitory activity (EC50 = 0.15 μM). A series of 2,4-diaminoquinazoline derivatives based on 4a as a lead compound were synthesized and subjected to structure–antidengue activity relationship studies. Among the series of 2,4-diaminoquinazoline derivative probed, 4o was observed to display both the highest antiviral potency (EC50 = 2.8 nM, SI > 1000) and an excellent pharmacokinetic profile.

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    2013-03-10 jklm09
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