A Quinazoline Nav1.7 Lead, Absolute Configuration Fixed by MicroED, Shows Oral Analgesia in Rodents
- Starting from a modest focused-library quinazoline hit, SAR across about twenty analogs gave a chiral lead with sub-micromolar potency and clear selectivity over Nav1.5.
- The absolute configuration was assigned by MicroED, so the active enantiomer is unambiguous without large crystals.
- The lead had acceptable oral exposure, reduced pain behavior in two rodent models, and was clean in a 44-target off-panel; Nav1.7-knockout neuron controls support on-target action.
💡 Points
Nav1.7 has burned a lot of programs on selectivity and translation, so a clean off-target panel plus knockout-neuron controls is what I'd look at first. Potency is still modest and the dose needed is high, so this is a starting scaffold rather than a candidate. The practical takeaway is MicroED: assigning chirality from nanocrystals of an early lead saves weeks of enantiomer chasing.