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Published on: October 11, 2013
Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication
Janice A Sindac1, Scott J Barraza, Craig J Dobry
1Vahlteich Medicinal Chemistry Core and ‡Department of Medicinal Chemistry, College of Pharmacy, §Departments of Internal Medicine and Microbiology and Immunology, ∥Department of Neurology, ⊥Department of Neurosurgery, University of Michigan , Ann Arbor, Michigan 48109, United States.
Abstract:
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.
Insights
New indole-2-carboxamides show improved potency against alphaviruses like western equine encephalitis virus (WEEV). These compounds demonstrate enhanced stability and blood-brain barrier penetration, offering potential for treating neurotropic alphavirus infections.
Area of Science:
- Virology
- Neuroscience
- Medicinal Chemistry
Background:
- Neurotropic alphaviruses cause severe encephalitis.
- Previous indole-2-carboxamides showed alphavirus replication inhibition.
Purpose of the Study:
- Develop more potent and stable indole-2-carboxamide inhibitors.
- Improve blood-brain barrier penetration for treating WEEV infections.
Main Methods:
- Developed novel indole-2-carboxamide analogues.
- Assessed WEEV replicon inhibition and metabolic stability.
- Utilized rhodamine123 uptake assay in MDR1-MDCKII cells to evaluate P-glycoprotein interaction.
- Conducted preliminary mouse pharmacokinetic (PK) studies.
Main Results:
- Achieved 10-fold increase in WEEV replicon potency.
- Increased metabolic half-lives up to 40-fold.
- Identified structural modifications reducing P-glycoprotein efflux.
- Demonstrated higher/longer plasma exposure and measurable brain drug levels in mice.
Conclusions:
- Further developed indole-2-carboxamides exhibit enhanced potency and stability.
- Optimized compounds show reduced P-glycoprotein interaction, improving brain penetration.
- These analogues represent promising candidates for treating neurotropic alphavirus encephalitis.
