The contribution of Na1.6 to the efficacy of voltage-gated sodium channel inhibitors in wild type and Na1.6 gain-of-function (GOF) mouse seizure control.

Background And Purpose: Inhibitors of voltage-gated sodium channels (Nas) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Na channels as a means of informing the development of improved antiseizure drugs.

Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of Na1.

NBI-921352, a first-in-class, Na1.6 selective, sodium channel inhibitor that prevents seizures in gain-of-function mice, and wild-type mice and rats.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na1.6 channels. Such a molecule provides a precision-medicine approach to target -related epilepsy syndromes (-RES), where gain-of-function (GoF) mutations lead to excess Na1.

Identification of aryl sulfonamides as novel and potent inhibitors of Na1.5.

We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of Na1.5. Unlike local anesthetics that are currently used for treatment of Long QT Syndrome 3 (LQT-3), the most potent compound (-)-6 in this series shows high selectivity over hERG and other cardiac ion channels and has a low brain to plasma ratio to minimize CNS side effects.

Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective Na1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy.

Nonselective antagonists of voltage-gated sodium (Na) channels have been long used for the treatment of epilepsies. The efficacy of these drugs is thought to be due to the block of sodium channels on excitatory neurons, primarily Na1.6 and Na1.

Progress in Understanding and Treating SCN2A-Mediated Disorders.

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel Na1.2.

Lessons learned from candidate drug attrition.

Rising expenditure in pharmaceutical R&D has not been matched by increased productivity. There is an urgent need to solve the current high levels of pipeline attrition. Changing the current failed model of drug discovery and development, in which high numbers of candidate drugs are produced and high attrition is accepted, is essential.

Experimental solubility profiling of marketed CNS drugs, exploring solubility limit of CNS discovery candidate.

We determined the experimental solubility of CNS marketed drugs. Of the 98 drugs measured, greater than 90% had solubility >10 μM in pH 7.4 buffer.

Real-time in situ Raman analysis of microwave-assisted organic reactions.

Integration of a Raman probe into a commercially available microwave synthesizer has demonstrated unprecedented utility in understanding chemical processes within the rapidly emerging field of microwave-assisted organic synthesis. The real-time spectral feedback afforded by this system has facilitated analysis of reaction mechanisms, reactive intermediates, and reaction kinetics via optical sampling through the sidewall of the sealed reaction vial within the microwave chamber. The feasibility, attributes, and limitations of the system are illustrated using amine coupling and Knoevenagel coupling example reactions.

Synthesis of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones as NMDA glycine-site antagonists.

Several members of the 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones (2) have been identified as being potent and selective NMDA glycine-site antagonists. Increasing size of the alkyl substituent on the alpha-carbon led to a progressive decrease in binding affinity. Some of these analogues possess improved drug-like properties such as cellular permeability, solubility and oral absorption.