Small-molecule eRF3a degraders rescue CFTR nonsense mutations by promoting premature termination codon readthrough.

The vast majority of people with cystic fibrosis (CF) are now eligible for CF transmembrane regulator (CFTR) modulator therapy. The remaining individuals with CF harbor premature termination codons (PTCs) or rare CFTR variants with limited treatment options. Although the clinical modulator response can be reliably predicted using primary airway epithelial cells, primary cells carrying rare CFTR variants are scarce.

PF-06526290 can both enhance and inhibit conduction through voltage-gated sodium channels.

Background And Purpose: Pharmacological agents that either inhibit or enhance flux of ions through voltage-gated sodium (Na ) channels may provide opportunities for treatment of human health disorders. During studies to characterize agents that modulate Na 1.3 function, we identified a compound that appears to exhibit both enhancement and inhibition of sodium ion conduction that appeared to be dependent on the gating state that the channel was in.

Discovery and in Vitro Optimization of 3-Sulfamoylbenzamides as ROMK Inhibitors.

Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit , this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles.

GI-530159, a novel, selective, mechanosensitive two-pore-domain potassium (K ) channel opener, reduces rat dorsal root ganglion neuron excitability.

Background And Purpose: TREK two-pore-domain potassium (K ) channels play a critical role in regulating the excitability of somatosensory nociceptive neurons and are important mediators of pain perception. An understanding of the roles of TREK channels in pain perception and, indeed, in other pathophysiological conditions, has been severely hampered by the lack of potent and/or selective activators and inhibitors. In this study, we describe a new, selective opener of TREK channels, GI-530159.

Highly potent and selective Na1.7 inhibitors for use as intravenous agents and chemical probes.

The discovery and selection of a highly potent and selective Na1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed.

Biophysical and Pharmacological Characterization of Nav1.9 Voltage Dependent Sodium Channels Stably Expressed in HEK-293 Cells.

The voltage dependent sodium channel Nav1.9, is expressed preferentially in peripheral sensory neurons and has been linked to human genetic pain disorders, which makes it target of interest for the development of new pain therapeutics. However, characterization of Nav1.

Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release.

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation.

Addition of a single methyl group to a small molecule sodium channel inhibitor introduces a new mode of gating modulation.

Background And Purpose: Aryl sulfonamide Nav 1.3 or Nav 1.7 voltage-gated sodium (Nav ) channel inhibitors interact with the Domain 4 voltage sensor domain (D4 VSD).

Pharmacological modulation of voltage-gated potassium channels as a therapeutic strategy.

Importance Of The Field: The human genome encodes at least 40 distinct voltage-gated potassium channel subtypes, which vary in regional expression, pharmacological and biophysical properties. Voltage-dependent potassium (Kv) channels help orchestrate many of the physiological and pathophysiological processes that promote and sometimes hinder the healthy functioning of our bodies.

Areas Covered In This Review: This review summarizes patent and scientific literature reports from the past decade highlighting the opportunities that Kv channels offer for the development of new therapeutic interventions for a wide variety of disorders.

Therapeutic potential of KCa3.1 blockers: recent advances and promising trends.

The Ca(2+)-activated K(+) channel K(Ca)3.1 regulates membrane potential and calcium signaling in erythrocytes, activated T and B cells, macrophages, microglia, vascular endothelium, epithelia, and proliferating vascular smooth muscle cells and fibroblasts. K(Ca)3.

Voltage-gated potassium channels as therapeutic targets.

The human genome encodes 40 voltage-gated K(+) channels (K(V)), which are involved in diverse physiological processes ranging from repolarization of neuronal and cardiac action potentials, to regulating Ca(2+) signalling and cell volume, to driving cellular proliferation and migration. K(V) channels offer tremendous opportunities for the development of new drugs to treat cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This Review discusses pharmacological strategies for targeting K(V) channels with venom peptides, antibodies and small molecules, and highlights recent progress in the preclinical and clinical development of drugs targeting the K(V)1 subfamily, the K(V)7 subfamily (also known as KCNQ), K(V)10.

Pharmacological removal of human ether-à-go-go-related gene potassium channel inactivation by 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574).

Human ether-à-go-go-related gene (hERG) potassium channel activity helps shape the cardiac action potential and influences its duration. In this study, we report the discovery of 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574), a potent and efficacious hERG channel activator with a unique mechanism of action. In whole-cell patch-clamp studies of recombinant hERG channels, ICA-105574 steeply potentiated current amplitudes more than 10-fold with an EC(50) value of 0.

The effect of kappa-opioid receptor agonists on tetrodotoxin-resistant sodium channels in primary sensory neurons.

Background: A non-opioid receptor-mediated inhibition of sodium channels in dorsal root ganglia (DRGs) by kappa-opioid receptor agonists (kappa-ORAs) has been reported to contribute to the antinociceptive actions in animals and humans. In this study, we examined structurally diverse kappa-ORAs for their abilities to inhibit tetrodotoxin-resistant (TTX-r) sodium channels in adult rat DRGs.

Methods: Whole-cell recordings of TTX-r sodium currents were performed on cultured adult rat DRGs.

Aryl sulfonamido tetralin inhibitors of the Kv1.5 ion channel.

Aryl sulfonamido tetralins based on lead compound 2a were synthesized and evaluated for Kv1.5 inhibitory activity. Several compounds having IC(50) values less then 0.

Aryl sulfonamido indane inhibitors of the Kv1.5 ion channel.

A collection of aryl sulfonamido indanes based on the lead compound 1 was synthesized and evaluated for Kv1.5 inhibitory activity. Kv1.

Aquaporins as targets for drug discovery.

Over the past decade, significant advances have been made in understanding how water moves in to and out of cells. Investigators have used molecular and structural biological techniques to show that nature has evolved specialized water-conducting proteins called aquaporins, which traverse biological membranes in the cells of animals, plants and even bacteria. It is becoming increasingly clear that these aquaporins have fundamental roles in normal human physiology and pathophysiology.

In vitro and in vivo characterization of a novel naphthylamide ATP-sensitive K+ channel opener, A-151892.

1. Openers of ATP-sensitive K(+) channels are of interest in several therapeutic indications including overactive bladder and other lower urinary tract disorders. This study reports on the in vitro and in vivo characterization of a structurally novel naphthylamide N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl]-acetamide (A-151892), as an opener of the ATP-sensitive potassium channels.

Structure-activity relationship of a novel class of naphthyl amide KATP channel openers.

We have discovered a novel series of N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl] amides that are potent openers of K(ATP) channels and investigated structure-activity relationships (SAR) around the 1,2-disubstituted naphthyl core. A-151892, a prototype compound of this series, was found to be a potent and efficacious potassium channel opener in vitro in transfected Kir6.2/SUR2B cells and pig bladder strips.

Electrophysiological analysis of heterologously expressed Kv and SK/IK potassium channels.

This unit describes protocols to aid investigators in determining the electrophysiological and pharmacological profile of heterologously expressed voltage or calcium-activated potassium channels belonging to the Kv1.x and SK/IK gene families. Protocols for data acquisition as well as analysis are provided.