ABSTRACT
BACKGROUND AND PURPOSE: Inhibitors of voltage-gated sodium channels (NaVs) 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 Nav 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 NaV1.6 alone or together with NaV1.2. These novel NaV inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding NaV1.6) and in wild-type mice. KEY RESULTS: Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures evoked by a 6-Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. CONCLUSIONS AND IMPLICATIONS: Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti-seizure medicines. Sparing the NaV1.1 channels of inhibitory interneurons did not compromise efficacy. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies.
ABSTRACT
Voltage-gated sodium channel (NaV) 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 NaV-targeting antiseizure medications nonselectively inhibit the brain channels NaV1.1, NaV1.2, and NaV1.6, which potentially limits the efficacy and therapeutic safety margins of these drugs. Here, we report on XPC-7724 and XPC-5462, which represent a new class of small molecule NaV-targeting compounds. These compounds specifically target inhibition of the NaV1.6 and NaV1.2 channels, which are abundantly expressed in excitatory pyramidal neurons. They have a > 100-fold molecular selectivity against NaV1.1 channels, which are predominantly expressed in inhibitory neurons. Sparing NaV1.1 preserves the inhibitory activity in the brain. These compounds bind to and stabilize the inactivated state of the channels thereby reducing the activity of excitatory neurons. They have higher potency, with longer residency times and slower off-rates, than the clinically used antiseizure medications carbamazepine and phenytoin. The neuronal selectivity of these compounds is demonstrated in brain slices by inhibition of firing in cortical excitatory pyramidal neurons, without impacting fast spiking inhibitory interneurons. XPC-5462 also suppresses epileptiform activity in an ex vivo brain slice seizure model, whereas XPC-7224 does not, suggesting a possible requirement of Nav1.2 inhibition in 0-Mg2+- or 4-AP-induced brain slice seizure models. The profiles of these compounds will facilitate pharmacological dissection of the physiological roles of NaV1.2 and NaV1.6 in neurons and help define the role of specific channels in disease states. This unique selectivity profile provides a new approach to potentially treat disorders of neuronal hyperexcitability by selectively downregulating excitatory circuits.
Subject(s)
Epilepsy , Voltage-Gated Sodium Channels , Humans , Neurons/metabolism , Voltage-Gated Sodium Channels/metabolism , Epilepsy/metabolism , Brain/metabolism , Seizures/drug therapy , Seizures/metabolism , Action Potentials/physiologyABSTRACT
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 ß-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors. Dimeric compounds were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary nonheme iron uptake in both rats and pigs yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiologic function of DMT1 in the gut. SIGNIFICANCE STATEMENT: This report introduces methodology to develop potent, gut-restricted inhibitors of divalent metal transporter 1 (DMT1) and identifies XEN602 as a suitable compound for in vivo studies. We also report novel animal models to quantify the inhibition of dietary uptake of iron in both rodents and pigs. This research shows that inhibition of DMT1 is a promising means to treat iron overload disorders.
Subject(s)
Iron Overload , Humans , Rats , Animals , Swine , Iron Overload/drug therapy , Iron/metabolism , Biological Transport , Iron-Binding Proteins/metabolism , Models, AnimalABSTRACT
NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC500.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for NaV1.1, 134 X for NaV1.2, 276 X for NaV1.7, and >583 Xfor NaV1.3, NaV1.4, and NaV1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.
Subject(s)
Epilepsy , NAV1.6 Voltage-Gated Sodium Channel , Animals , Gain of Function Mutation , Mice , Mutation , NAV1.6 Voltage-Gated Sodium Channel/genetics , Neurons/physiology , Rats , Sodium , Sodium Channel Blockers/pharmacologyABSTRACT
We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of NaV1.5. 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. Compound (-)-6 is also effective inshortening prolonged action potential durations (APDs) in a pharmacological model of LQT-3 syndrome in pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Unlike most aryl sulfonamide NaV inhibitors that bind to the channel voltage sensors, these NaV1.5 inhibitors bind to the local anesthetic binding site in the central pore of the channel.
Subject(s)
NAV1.5 Voltage-Gated Sodium Channel/metabolism , Sulfonamides/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
Nav1.7 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 (1) and GDC-0310 (2), selective Nav1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3. This resulted in the discovery of GDC-0276 (1), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Nav1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Nav selectivity and pharmacokinetic profile over 1.
Subject(s)
Azetidines/pharmacology , Benzamides/pharmacology , Drug Discovery , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Sulfonamides/pharmacology , Voltage-Gated Sodium Channel Blockers/pharmacology , Animals , Azetidines/chemistry , Azetidines/pharmacokinetics , Benzamides/chemistry , Benzamides/pharmacokinetics , Cells, Cultured , HEK293 Cells , Humans , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/pharmacology , Rats, Sprague-Dawley , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Voltage-Gated Sodium Channel Blockers/chemistry , Voltage-Gated Sodium Channel Blockers/pharmacokineticsABSTRACT
Nonselective antagonists of voltage-gated sodium (NaV) 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 NaV1.6 and NaV1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of NaV1.6, while sparing NaV1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of NaV1.2 may complement the anticonvulsant activity of NaV1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective NaV1.6 inhibitors, which also displayed potent block of NaV1.2. Optimization focused on increasing selectivity over NaV1.1, improving metabolic stability, reducing active efflux, and addressing a pregnane X-receptor liability. We obtained compounds 30-32, which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock seizure assay.
Subject(s)
Amides/chemistry , Central Nervous System/metabolism , Epilepsy/drug therapy , NAV1.6 Voltage-Gated Sodium Channel/metabolism , Sodium Channel Blockers/metabolism , Sodium Channel Blockers/pharmacology , Animals , Dogs , Hep G2 Cells , Humans , Madin Darby Canine Kidney Cells , Mice , Models, Molecular , NAV1.6 Voltage-Gated Sodium Channel/chemistry , Protein Domains , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/therapeutic use , Structure-Activity RelationshipABSTRACT
Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Nav1.7 inhibitors was discovered. Early optimization focused on improvement of potency through refinement of the low energy ligand conformation and mitigation of high in vivo clearance. An in vitro hepatotoxicity hazard was identified and resolved through optimization of lipophilicity and lipophilic ligand efficiency to arrive at GNE-616 (24), a highly potent, metabolically stable, subtype selective inhibitor of Nav1.7. Compound 24 showed a robust PK/PD response in a Nav1.7-dependent mouse model, and site-directed mutagenesis was used to identify residues critical for the isoform selectivity profile of 24.
Subject(s)
NAV1.7 Voltage-Gated Sodium Channel/chemistry , Sulfonamides/chemistry , Voltage-Gated Sodium Channel Blockers/chemistry , Analgesics/chemistry , Analgesics/metabolism , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Binding Sites , Cell Line , Cell Survival/drug effects , Chronic Pain/drug therapy , Chronic Pain/pathology , Dogs , Half-Life , Humans , Ligands , Male , Mice , Molecular Docking Simulation , Mutagenesis, Site-Directed , NAV1.7 Voltage-Gated Sodium Channel/genetics , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Rats , Structure-Activity Relationship , Sulfonamides/metabolism , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Voltage-Gated Sodium Channel Blockers/metabolism , Voltage-Gated Sodium Channel Blockers/pharmacology , Voltage-Gated Sodium Channel Blockers/therapeutic useABSTRACT
Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for NaV1.7 over NaV1.5 and highly efficacious in in vivo models of pain and hNaV1.7 target engagement. An analysis of the physicochemical properties of literature NaV1.7 inhibitors suggested that acyl sulfonamides with high fsp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against NaV1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNaV1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the NaV1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious NaV1.7 inhibitors reported to date.
Subject(s)
Analgesics/chemistry , NAV1.7 Voltage-Gated Sodium Channel/chemistry , Sulfonamides/chemistry , Voltage-Gated Sodium Channel Blockers/chemistry , Analgesics/metabolism , Analgesics/therapeutic use , Animals , Binding Sites , Drug Design , Half-Life , Humans , Male , Mice , Mice, Transgenic , Microsomes, Liver/metabolism , Molecular Docking Simulation , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Pain/chemically induced , Pain/drug therapy , Pain/pathology , Protein Structure, Tertiary , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/metabolism , Sulfonamides/therapeutic use , Voltage-Gated Sodium Channel Blockers/metabolism , Voltage-Gated Sodium Channel Blockers/therapeutic useABSTRACT
Selective block of NaV1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several NaV1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC50. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma.
Subject(s)
Analgesics/therapeutic use , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Neuralgia/drug therapy , Sodium Channel Blockers/therapeutic use , Sulfonamides/therapeutic use , Analgesics/pharmacokinetics , Animals , Binding Sites , Cells, Cultured , HEK293 Cells , Humans , Inhibitory Concentration 50 , Mice , NAV1.7 Voltage-Gated Sodium Channel/chemistry , Protein Binding , Sodium Channel Blockers/pharmacokinetics , Sulfonamides/pharmacokineticsABSTRACT
The sodium channel NaV1.7 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 NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of NaV1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.
Subject(s)
Drug Design , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Pain/drug therapy , Sulfonamides/chemistry , Sulfonamides/pharmacology , Voltage-Gated Sodium Channel Blockers/chemistry , Voltage-Gated Sodium Channel Blockers/pharmacology , Amino Acid Sequence , Animals , Dogs , Drug Stability , Humans , Kinetics , Mice , Molecular Conformation , Pain/metabolism , Rats , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use , Voltage-Gated Sodium Channel Blockers/pharmacokinetics , Voltage-Gated Sodium Channel Blockers/therapeutic useABSTRACT
Many ion channels, including Nav1.7, Cav1.3, and Kv1.3, are linked to human pathologies and are important therapeutic targets. To develop efficacious and safe drugs, subtype-selective modulation is essential, but has been extremely difficult to achieve. We postulate that this challenge is caused by the poor assay design, and investigate the Nav1.7 membrane potential assay, one of the most extensively employed screening assays in modern drug discovery. The assay uses veratridine to activate channels, and compounds are identified based on the inhibition of veratridine-evoked activities. We show that this assay is biased toward nonselective pore blockers and fails to detect the most potent, selective voltage-sensing domain 4 (VSD4) blockers, including PF-05089771 (PF-771) and GX-936. By eliminating a key binding site for pore blockers and replacing veratridine with a VSD-4 binding activator, we directed the assay toward non-pore-blocking mechanisms and discovered Nav1.7-selective chemical scaffolds. Hence, we address a major hurdle in Nav1.7 drug discovery, and this mechanistic approach to assay design is applicable to Cav3.1, Kv1.3, and many other ion channels to facilitate drug discovery.
Subject(s)
Drug Discovery/methods , Molecular Targeted Therapy , Voltage-Gated Sodium Channel Blockers/analysis , Animals , High-Throughput Screening Assays , Humans , Insect Proteins , Membrane Potentials , NAV1.7 Voltage-Gated Sodium Channel/drug effects , NAV1.7 Voltage-Gated Sodium Channel/genetics , Rats , Veratridine , Wasp VenomsABSTRACT
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. This added contextual setting goes beyond identification of modifier genes and needs to encompass microenvironmental factors which can differentially affect the phenotype of patients harboring the same mutation. The Early Infantile Epileptic Encephalopathies (EIEEs) associated with de novo mutations in voltage gated sodium channels are interesting case studies that include examples of genotype-phenotype mismatches. With EIEE11, associated with mutations in SCN2A, incorporation of biological/pathophysiological contexts are helpful in clarifying the apparent genotype-phenotype mismatches which are captured with more reductionist approaches.
Subject(s)
Mutation , NAV1.2 Voltage-Gated Sodium Channel/genetics , Severity of Illness Index , Spasms, Infantile/genetics , Genetic Association Studies , Genotype , Humans , Mutation, Missense , Phenotype , Spasms, Infantile/etiologyABSTRACT
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 NaV1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of NaV1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a NaV1.9 mutation (L1302F) that is associated with insensitivity to pain. We investigated the effects of L1302F and a previously reported mutation (L811P) on neuronal excitability. In transfected heterologous cells, the L1302F mutation caused a large hyperpolarizing shift in the voltage-dependence of activation, leading to substantially enhanced overlap between activation and steady-state inactivation relationships. In transfected small rat dorsal root ganglion neurons, expression of L1302F and L811P evoked large depolarizations of the resting membrane potential and impaired action potential generation. Therefore, our findings implicate a cellular loss of function as the basis for impaired pain sensation. We further demonstrated that a U-shaped relationship between the resting potential and the neuronal action potential threshold explains why NaV1.9 mutations that evoke small degrees of membrane depolarization cause hyperexcitability and familial episodic pain disorder or painful neuropathy, while mutations evoking larger membrane depolarizations cause hypoexcitability and insensitivity to pain.
Subject(s)
Action Potentials/genetics , Ion Channel Gating/genetics , Mutation, Missense , Neurons/metabolism , Pain Insensitivity, Congenital , Adult , Amino Acid Substitution , Female , Humans , NAV1.9 Voltage-Gated Sodium Channel/genetics , NAV1.9 Voltage-Gated Sodium Channel/metabolism , Pain Insensitivity, Congenital/genetics , Pain Insensitivity, Congenital/metabolism , Pain Insensitivity, Congenital/physiopathologyABSTRACT
We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNaV1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of NaV1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNaV1.7 as a drug target for the treatment of pain.
ABSTRACT
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. Targeting the human Nav1.7 channel involved in pain perception, we present a protein-engineering strategy that has allowed us to determine crystal structures of a novel receptor site in complex with isoform-selective antagonists. GX-936 and related inhibitors bind to the activated state of voltage-sensor domain IV (VSD4), where their anionic aryl sulfonamide warhead engages the fourth arginine gating charge on the S4 helix. By opposing VSD4 deactivation, these compounds inhibit Nav1.7 through a voltage-sensor trapping mechanism, likely by stabilizing inactivated states of the channel. Residues from the S2 and S3 helices are key determinants of isoform selectivity, and bound phospholipids implicate the membrane as a modulator of channel function and pharmacology. Our results help to elucidate the molecular basis of voltage sensing and establish structural blueprints to design selective Nav channel antagonists.
Subject(s)
NAV1.7 Voltage-Gated Sodium Channel/chemistry , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Amino Acid Sequence , Cell Membrane/chemistry , Crystallization/methods , Crystallography, X-Ray , DNA Mutational Analysis , Humans , Models, Molecular , Molecular Sequence Data , NAV1.7 Voltage-Gated Sodium Channel/genetics , Pain Perception/drug effects , Protein Engineering , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/chemistry , Protein Structure, Secondary , Protein Structure, TertiaryABSTRACT
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. It is suggested that physicians employ personal social values in their EOL medical coping, because they have to cope with existential dilemmas posed by the mystery of death, and left unresolved by medical decision making mechanisms such as advanced directives and hospital ethics committees.
Subject(s)
Attitude of Health Personnel , Decision Making , Physicians/psychology , Social Values , Terminal Care/psychology , Adult , Age Factors , Female , Humans , Israel , Male , Middle Aged , Physicians/ethics , Religion , Terminal Care/ethicsABSTRACT
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 Nav1.7 since 2010 until May, 2014. We have classified the patents into three categories as follows: small molecules with well-defined molecular selectivity among sodium channel isoforms; biologicals with well-defined molecular selectivity; and, small molecules that inhibit Nav1.7 with unknown molecular selectivity. Most of the review is dedicated to small molecule selective compounds.
Subject(s)
Drug Approval , Drug Industry/legislation & jurisprudence , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Patents as Topic , Voltage-Gated Sodium Channel Blockers/chemistry , Voltage-Gated Sodium Channel Blockers/pharmacology , Drug Approval/statistics & numerical data , Humans , Molecular Structure , NAV1.7 Voltage-Gated Sodium Channel/genetics , Patents as Topic/statistics & numerical dataABSTRACT
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 Nav1.7 in pain signaling. Herein, we report the design and synthesis of a novel series of benzenesulfonamide-based Nav1.7 inhibitors. Structural-activity relationship (SAR) studies were undertaken towards improving Nav1.7 activity and minimizing CYP inhibition. These efforts resulted in the identification of compound 12k, a highly potent Nav1.7 inhibitor with a thousand-fold selectivity over Nav1.5 and negligible CYP inhibition.