期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 22, 页码 9222-9241出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm401330r
关键词
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资金
- NIH [R01 A1089417]
- UM Rackham Merit Scholarship
- Ella and Hans Vahlteich Fund
- Beverly Vahlteich Delaney
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 repliton 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 analogues 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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