Optimization of Novel Indole-2-carboxamide Inhibitors of Neurotropic Alphavirus Replication

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 r...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-11, Vol.56 (22), p.9222-9241
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents - chemistry
Antiviral Agents - metabolism
Antiviral Agents - pharmacokinetics
Antiviral Agents - pharmacology
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Blood-Brain Barrier - drug effects
Blood-Brain Barrier - metabolism
Cell Line
Drug Design
Encephalitis Virus, Western Equine - drug effects
Encephalitis Virus, Western Equine - physiology
Humans
Hydrophobic and Hydrophilic Interactions
Indoles - chemistry
Indoles - metabolism
Indoles - pharmacokinetics
Indoles - pharmacology
Mice
Molecular Weight
Solubility
Structure-Activity Relationship
Virus Replication - drug effects
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401330r