1401618-71-0Relevant articles and documents
Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication
Sindac, Janice A.,Barraza, Scott J.,Dobry, Craig J.,Xiang, Jianming,Blakely, Pennelope K.,Irani, David N.,Keep, Richard F.,Miller, David J.,Larsen, Scott D.
, p. 9222 - 9241 (2014/01/06)
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 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.