Discovery of mCMV280: An Oral Ectoparasiticide in the Isoxazoline Class with Reduced Mammalian Brain Exposure

Vector-borne diseases represent a significant global health concern, and effective vector control in animals often involves using orally administered drugs that kill arthropod vectors of human pathogens. Isoxazoline ectoparasiticides may have promise in humans if they can be optimized for safe use due to their selectivity for invertebrate over mammalian ion channels. Yet, isoxazolines can cause neurological side effects due to their ability to cross the blood brain barrier, and thus, we synthesized novel isoxazolines with improved physiochemical properties to reduce brain exposure without reducing toxicity to arthropod pests. Our medicinal chemistry campaigns led to the discovery of lead compound mCMV280 that is 3× more toxic to ticks and equitoxic to mosquitoes, with an ∼5× reduction in mammalian brain exposure and an ∼8× lower brain-to-plasma ratio compared to fluralaner. These findings highlight the promise of new isoxazoline scaffolds for safer and more effective drug-based vector control strategies in humans.