Swapping a carboxyl for a sulfone yields a more drug-like RORγt inverse agonist
- An earlier carboxyl-bearing biaryl urea worked in a mouse psoriasis model but had weak microsomal stability and only modest oral exposure.
- The team moved to sulfone-containing biaryl ureas, arriving at YW-089, a potent and selective RORγt inverse agonist that also blocks Th17 cell activity.
- Metabolic stability improved across species and oral exposure was good in mouse, rat and dog.
- Efficacy held up in two mouse psoriasis models, supporting preclinical progression.
💡 Points Based on the abstract
Dropping the carboxyl for a sulfone is a sensible way to escape acid-driven clearance and permeability issues, but a sulfone is no acid mimic, so the binding mode must have changed. I'd want a co-crystal showing what replaced the polar contact, plus longer tox work, since this target class has a history of safety questions.
📄 Paper · Journal of Medicinal Chemistry ↗ Identification of Novel RORγt Inverse Agonist YW-089 as a Preclinical Candidate for the Treatment of Autoimmune Diseases