Suzetrigine

Suzetrigine is an inhibitor of voltage-gated sodium channel 1.8 (Nav1.8; IC50 = 0.7 nM for the human channel).1 It is selective for Nav1.8 over a panel of eight additional voltage-gated sodium channels (IC50s = >10,000 nM for all).WARNING This product is not for human or veterinary use.

The synthesis of Suzetrigine (VX-548) revolves around the highly stereoselective construction of its tetrahydropyran core. A typical synthetic route begins with a chiral starting material (e.g., a chiral epoxide) that undergoes a stereoselective addition reaction with a fluoroaryllithium reagent, introducing a phenyl group and a trifluoromethyl group. Subsequently, a nucleophilic cyclization reaction forms the crucial tetrahydropyran ring, thus determining the correct configuration of the four stereocenters. Subsequent steps involve standard organotransformation reactions, such as cross-coupling reactions (e.g., the Suzuki coupling reaction), to introduce the pyridine moiety, ultimately yielding the final Suzetrigine product via deprotection and salt formation.

[1] JIM JONES. Selective Inhibition of NaV1.8 with VX-548 for Acute Pain.[J]. New England Journal of Medicine, 2023, 389 5: 393-405. DOI: 10.1056/nejmoa2209870