Aminopyrimidine NaV1.7 probe inhibits resting and inactivated states almost equally
- An automated patch-clamp screening cascade, built to deprioritize classic local-anesthetic pore binders, yielded an aminopyrimidine hit that was optimized into compound 6.
- Compound 6 combined balanced resting- and inactivated-state potency, selectivity over NaV1.5 and a tetrodotoxin-like isoform profile that includes NaV1.1.
- SAR pointed to the aminopyrimidine core and a methylene-linked aniline as key determinants of this profile.
💡 Points
State dependence is a leading suspect for why NaV1.7 programs keep failing clinically, so a probe that blocks resting and inactivated states alike is a good way to test that hypothesis. NaV1.1 activity is a flag for seizure-related liability, and I'd want a binding-site assignment before reading too much into the profile.
A Nontoxin Aminopyrimidine Probe for Near State-Independent Na V 1.7 Inhibition ↗