Discovery of novel cyclopentane carboxylic acids as potent and selective inhibitors of Na1.7.

Discovery efforts leading to the identification of cyclopentane carboxylic acid 31, a potent inhibitor of Na1.7 that showed high selectivity over Na1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein.

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.

Molecular Pharmacology of Selective Na1.6 and Dual Na1.6/Na1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo.

Voltage-gated sodium channel (Na) inhibitors are used to treat neurological disorders of hyperexcitability such as epilepsy. These drugs act by attenuating neuronal action potential firing to reduce excitability in the brain. However, all currently available Na-targeting antiseizure medications nonselectively inhibit the brain channels Na1.

Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1: Preclinical Efficacy against Iron Overload and Safety Evaluation.

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or -thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors.

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.

Discovery of Acyl-sulfonamide Na1.7 Inhibitors GDC-0276 and GDC-0310.

Na1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 () and GDC-0310 (), selective Na1.

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.

Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (Na) 1.7 with Potent Analgesic Activity.

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide Na1.7 inhibitors that are selective for Na1.7 over Na1.

Selective Na1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain.

Selective block of Na1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several Na1.

Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3- a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNa1.7 Inhibitors for the Treatment of Pain.

The sodium channel Na1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of Na1.

Mechanism-specific assay design facilitates the discovery of Nav1.7-selective inhibitors.

Many ion channels, including Nav1.7, Cav1.3, and Kv1.

Integration of biological/pathophysiological contexts to help clarify genotype-phenotype mismatches in monogenetic diseases. Childhood epilepsies associated with SCN2A as a case study.

Monogenetic diseases offer clear human validation for launching drug discovery programs in Pharma designed to develop important new medicines for unmet medical needs. However, mismatches in the genotype-phenotype of presenting patients complicate both the preclinical 'research target profile' and the clinical development strategy. Additional biological and pathophysiological data associated with the identified mutations are necessary for more optimal prosecution of these drug discovery programs.

Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability.

Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.

Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist.

Voltage-gated sodium (Nav) channels propagate action potentials in excitable cells. Accordingly, Nav channels are therapeutic targets for many cardiovascular and neurological disorders. Selective inhibitors have been challenging to design because the nine mammalian Nav channel isoforms share high sequence identity and remain recalcitrant to high-resolution structural studies.

Inhibitors of voltage-gated sodium channel Nav1.7: patent applications since 2010.

There has been intense interest in developing inhibitors of the sodium channel Nav1.7 because genetic studies have established very strong validation for the efficacy to alleviate both inflammatory and neuropathic pain. This review summarizes patent applications targeting Nav1.

The discovery of benzenesulfonamide-based potent and selective inhibitors of voltage-gated sodium channel Na(v)1.7.

The voltage gated sodium channel Nav1.7 represents an interesting target for the treatment of pain. Human genetic studies have identified the crucial role of Nav1.

Social values as an independent factor affecting end of life medical decision making.

Research shows that the physician's personal attributes and social characteristics have a strong association with their end-of-life (EOL) decision making. Despite efforts to increase patient, family and surrogate input into EOL decision making, research shows the physician's input to be dominant. Our research finds that physician's social values, independent of religiosity, have a significant association with physician's tendency to withhold or withdraw life sustaining, EOL treatments.

Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker.

Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli.

Targeting voltage-gated sodium channels for treating neuropathic and inflammatory pain.

Voltage-gated sodium channels (Na(V)) are well validated targets for treating pain based both on human genetics and clinical experience. Consequently, there is an extensive literature on sodium channels for the treatment of pain and a number of excellent and thorough reviews have recently appeared; a selection of these is provided. This review does not attempt to evaluate all aspects of the studies in this area, but rather will focuses on several key issues that are incompletely addressed in prior reviews or that represent very recent additions to the literature.

Discovery of potent and use-dependent sodium channel blockers for treatment of chronic pain.

A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pain is reported. Systematic structure-activity relationship studies, starting with compound 1, led to identification of potent analogs that displayed use-dependent block of sodium channels, were efficacious in pain models in vivo, and most importantly, were devoid of activity against the cardiac potassium channel hERG.