Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication.
Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication.
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DOI：
10.1021/jm401330r
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发表时间：
2013-11-27
影响因子：
7.3
通讯作者：
Larsen SD
中科院分区：
文献类型：
--
作者：
Sindac JA;Barraza SJ;Dobry CJ;Xiang J;Blakely PK;Irani DN;Keep RF;Miller DJ;Larsen SD
嗜神经性甲病毒，包括西部马脑炎病毒 (WEEV) 和摩根堡病毒，是蚊媒病原体，可感染中枢神经系统，导致急性和可能致命的脑炎。我们之前报道了一系列新型吲哚-2-甲酰胺作为甲病毒复制抑制剂，其中一种可以保护小鼠免受神经适应性辛德比斯病毒感染。我们在此描述了该系列的进一步开发，使 WEEV 复制子测定的效力提高了 10 倍，并将小鼠肝微粒体的半衰期延长了 40 倍。在 MDR1-MDCKII 细胞中使用罗丹明 123 摄取测定，我们能够识别出显着降低 P-糖蛋白（血脑屏障的关键外排转运蛋白）识别的结构修饰。在一项初步的小鼠 PK 研究中，我们能够证明两种新的类似物比我们之前的先导药物可以实现更高和/或更长的血浆药物暴露，并且一种化合物在大脑中达到了可测量的药物水平。
Neurotropic alphaviruses, which include western equine encephalitis virus (WEEV) and Fort Morgan virus, are mosquito-borne pathogens that infect the central nervous system causing acute and potentially fatal encephalitis. We previously reported a novel series of indole-2-carboxamides as alphavirus replication inhibitors, one of which conferred protection against neuroadapted Sindbis virus infection in mice. We describe here further development of this series resulting in 10-fold improvement in potency in a WEEV replicon assay and up to 40-fold increases in half-lives in mouse liver microsomes. Using a rhodamine123 uptake assay in MDR1-MDCKII cells we were able to identify structural modifications that markedly reduce recognition by P-glycoprotein, the key efflux transporter at the blood brain barrier. In a preliminary mouse PK study we were able to demonstrate that two new analogs could achieve higher and/or longer plasma drug exposures than our previous lead, and that one compound achieved measurable drug levels in the brain.
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影响因子：
6.5
作者：
Larsen, Scott D.;Wilson, Michael W.;Shayman, James A.
通讯作者：
Shayman, James A.
影响因子：
7.4
作者：
Bevan, CD;Lloyd, RS
通讯作者：
Lloyd, RS
影响因子：
6.4
作者：
Peng, Weiping;Peltier, Daniel C.;Miller, David J.
通讯作者：
Miller, David J.
DOI：
10.1016/b978-012369520-8.50008-5
发表时间：
2008-01-01
期刊：
DRUG-LIKE PROPERTIES: CONCEPTS, STRUCTURE DESIGN AND METHODS
影响因子：
--
作者：
Kerns, Edward H.;Di, Li
通讯作者：
Di, Li
影响因子：
6.7
作者：
Di, L;Kerns, EH;Carter, GT
通讯作者：
Carter, GT