pynegabine (HN37) / Hainan Haiyao, Shanghai Inst. of Materia Medica - LARVOL DELTA

Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5. (PubMed, Proc Natl Acad Sci U S A) - "Here, we report cryoelectron microscopy structures of the human KCNQ5-calmodulin (CaM) complex in the apo, PIP2-bound, and both PIP2- and the activator HN37-bound states in either a closed or an open conformation. In the closed conformation, a PIP2 molecule binds in the middle of the groove between two adjacent voltage-sensing domains (VSDs), whereas in the open conformation, one additional PIP2 binds to the interface of VSD and the pore domain, accompanying structural rearrangement of the cytosolic domain of KCNQ and CaM. The structures, along with electrophysiology analyses, reveal the two different binding modes of PIP2 and elucidate the PIP2 activation mechanism of KCNQ5."

Journal

Electrophysiological Abnormalities and Pharmacological Corrections of Pathogenic Missense Variants in KCNQ3. (PubMed, Neurosci Bull) - "The LOF mutations were reversed by the application of Pynegabine (HN37), a KCNQ opener, while the GOF mutation responded well to Amitriptyline (AMI), a KCNQ inhibitor. These findings provide essential insights into the pathogenic mechanisms underlying KCNQ3-related disorders and may inform clinical decision-making."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Psychiatry

Targeting Kv7 Potassium Channels for Epilepsy. (PubMed, CNS Drugs) - "Ezogabine (retigabine), the first Kv7.2/3 activator introduced in 2011 for the treatment of focal seizures, was withdrawn from the market in 2017 due to declining use after discovery of its association with pigmentation changes in the retina, skin, and mucosae...Another Kv7.2/3 activator, BHV-7000, has completed phase I studies in healthy subjects, with excellent tolerability at plasma drug concentrations that exceed the median effective concentrations in a preclinical model of anticonvulsant activity, but no efficacy data in patients with epilepsy are available to date. Among other Kv7.2/3 activators in clinical development as potential antiseizure medications, pynegabine and CB-003 have completed phase I safety and pharmacokinetic studies, but results have not been yet reported. Overall, interest in targeting Kv7 channels for the treatment of epilepsy and for other indications remains strong. Future breakthroughs in this area could come from exploitation of mechanistic..."

Journal • Review • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Pediatrics • Psychiatry

A randomized, double-blind, placebo-controlled, dose-escalating phase IIa trial to evaluate the safety, tolerability, efficacy, and pharmacokinetics of multiple oral doses of Pynegabine tablets as add-on therapy in patients with focal epilepsy. (PubMed, CNS Neurosci Ther) - "Data from the study will be used to evaluate the safety, tolerability, efficacy, and pharmacokinetics of Pynegabine tablets as add-on therapy for focal epilepsy."

Clinical • Journal • P2a data • PK/PD data • CNS Disorders • Epilepsy

Ligand activation mechanisms of human KCNQ2 channel. (PubMed, Nat Commun) - "The activator-bound structures, along with electrophysiology analyses, reveal the binding modes of two CBD, one PIP, and two HN37 molecules in each KCNQ2 subunit, and elucidate their activation mechanisms on the KCNQ2 channel. These structures may guide the development of antiepileptic drugs and analgesics that target KCNQ2."

Journal • Pain

Three-Step Synthesis of the Antiepileptic Drug Candidate Pynegabine. (PubMed, Molecules) - "Pynegabine, an antiepileptic drug candidate in phase I clinical trials, is a structural analog of the marketed drug retigabine with improved chemical stability, strong efficacy, and a better safety margin. To improve the feasibility of drug production, we developed a concise, three-step process using unconventional methoxycarbonylation and highly efficient Buchwald-Hartwig cross coupling. The new synthetic route generated pynegabine at the decagram scale without column chromatographic purification and avoided the dangerous manipulation of hazardous reagents."

Journal

Functional characterization and in vitro pharmacological rescue of KCNQ2 pore mutations associated with epileptic encephalopathy. (PubMed, Acta Pharmacol Sin) - "When co-expressed with KCNQ2-WT and KCNQ3 (1:1:2), the currents at 0 mV of these mutations were decreased by 30%-70% compared to the KCNQ2/3 channel, which could be significantly rescued by applying KCNQ openers including the approved antiepileptic drug retigabine (RTG, 10 μM), as well as two candidates subjected to clinical trials, pynegabine (HN37, 1 μM) and XEN1101 (1 μM). These newly identified pathologic variants enrich the KCNQ2-DEE mutation hotspots in the pore-forming domain. This electrophysiological study provides a rational basis for personalized therapy with KCNQ openers in DEE patients carrying loss-of-function (LOF) mutations in KCNQ2."

Journal • Preclinical • CNS Disorders • Epilepsy