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

## TL;DR

A new oral ectoparasiticide, mCMV280, was developed with reduced brain exposure in mammals while maintaining effectiveness against ticks and mosquitoes.

## Contribution

The novel isoxazoline compound mCMV280 shows improved safety and efficacy for potential human use in vector control.

## Key findings

- mCMV280 is 3× more toxic to ticks and equally toxic to mosquitoes.
- mCMV280 has ∼5× lower mammalian brain exposure compared to fluralaner.
- The brain-to-plasma ratio of mCMV280 is ∼8× lower than fluralaner.

## Abstract

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.