Discovery of HN37 as a Potent and Chemically Stable Antiepileptic Drug Candidate

We
previously reported that P-retigabine (P-RTG), a retigabine
(RTG) analogue bearing a propargyl group at the nitrogen atom in the
linker of RTG, displayed moderate anticonvulsant efficacy. Recently,
our further efforts led to the discovery of HN37 (pynegabine),
which demonstrated satisfactory chemical stability upon deleting the
ortho liable −NH2 group and installing two adjacent
methyl groups to the carbamate motif. HN37 exhibited
enhanced activation potency toward neuronal Kv7 channels and high in vivo efficacy in a range of pre-clinical seizure models,
including the maximal electroshock test and a 6 Hz model of pharmacoresistant
limbic seizures. With its improved chemical stability, strong efficacy,
and better safety margin, HN37 has progressed to clinical
trial in China for epilepsy treatment.