Ion channels
10 articles
Horse TASK1 channel emerges as atrial-selective AF target
- TASK1 potassium channels are an atrial-selective antiarrhythmic target, but their role in horses, where atrial fibrillation is the commonest significant arrhythmia, was unknown.
- In oocytes, equine and human TASK1 were structurally conserved with similar background currents, though drug potency differed somewhat.
- Equine expression was concentrated in atrial and nodal tissue, minimal in ventricle; the in vivo ketodoxapram result is truncated in the source.
Would I take this forward? A conserved channel with atrial-skewed expression is a reasonable start, but expression isn't native current, and ketodoxapram, a doxapram derivative, isn't a clean probe. Before crediting any rhythm effect to TASK1, I'd want its selectivity against other K2P and cardiac channels. With the in vivo readout cut off, the horse-as-AF-model case stays open.
Antibody blocking the ZIP12 zinc importer curbs pulmonary artery cell remodeling and shows early clinical tolerability
- ZIP12 is a zinc importer elevated in remodeled pulmonary arterioles in PAH; raising it in human smooth muscle cells increased free intracellular zinc and drove proliferation, while knockdown eased disease in rodents.
- The humanized antibody APL-9796 restored zinc levels and dampened proliferation, cytoskeletal change and contractility in patient-derived fibroblasts, smooth muscle cells and engineered artery tissue.
- In humanized Slc39a12 rats it improved cardiopulmonary readouts in a dose-dependent way, and it was well tolerated in phase 1 studies; transcriptomics implicated AMPK, PPAR and PI3K-Akt pathways.
Upregulation in human tissue and rodent knockdown support ZIP12, but without human loss-of-function genetics the validity case stays correlative. The humanized rat is also a convenient fit for the antibody, and the readouts do not show how much ZIP12 is engaged in remodeled arterioles. Phase 1 tolerability is not efficacy, so the translational gap in PAH remains wide open.
Targeting ZIP12-mediated Zn2+ signaling as a treatment for pulmonary hypertension ↗
Aminopyrimidine NaV1.7 probe inhibits resting and inactivated states almost equally
- An automated patch-clamp screening cascade, built to deprioritize classic local-anesthetic pore binders, yielded an aminopyrimidine hit that was optimized into compound 6.
- Compound 6 combined balanced resting- and inactivated-state potency, selectivity over NaV1.5 and a tetrodotoxin-like isoform profile that includes NaV1.1.
- SAR pointed to the aminopyrimidine core and a methylene-linked aniline as key determinants of this profile.
State dependence is a leading suspect for why NaV1.7 programs keep failing clinically, so a probe that blocks resting and inactivated states alike is a good way to test that hypothesis. NaV1.1 activity is a flag for seizure-related liability, and I'd want a binding-site assignment before reading too much into the profile.
A Nontoxin Aminopyrimidine Probe for Near State-Independent Na V 1.7 Inhibition ↗
Cinchona-derived ammonium salts give long-lasting, sensory-selective nerve block
- Ammonium salts built on natural cinchona alkaloids were explored as local anesthetics; the bicyclic quincoridine skeleton beat acyclic and monocyclic analogues.
- Lead CLA-1-3 blocked the rat sciatic nerve for more than 50 hours and potently inhibited voltage-gated sodium channels.
- A second compound, CLA-3-5, gave a sensory-selective block lasting up to about 3 hours at 0.30–0.60% concentration.
Duration is the headline, but the permanently charged ammonium is the more interesting design choice: it should slow washout from the injection site, which probably explains the long action. For anything that lasts over 50 hours, though, I'd look at local neurotoxicity and myotoxicity data before the efficacy curves.
Cinchona Alkaloids-Derived Ammonium Salts for Long-Acting and Sensory-Selective Nerve Blockades ↗
A Quinazoline Nav1.7 Lead, Absolute Configuration Fixed by MicroED, Shows Oral Analgesia in Rodents
- Starting from a modest focused-library quinazoline hit, SAR across about twenty analogs gave a chiral lead with sub-micromolar potency and clear selectivity over Nav1.5.
- The absolute configuration was assigned by MicroED, so the active enantiomer is unambiguous without large crystals.
- The lead had acceptable oral exposure, reduced pain behavior in two rodent models, and was clean in a 44-target off-panel; Nav1.7-knockout neuron controls support on-target action.
Nav1.7 has burned a lot of programs on selectivity and translation, so a clean off-target panel plus knockout-neuron controls is what I'd look at first. Potency is still modest and the dose needed is high, so this is a starting scaffold rather than a candidate. The practical takeaway is MicroED: assigning chirality from nanocrystals of an early lead saves weeks of enantiomer chasing.
Novel TRPM7 Inhibitors Curb Breast Cancer Growth and Invasion in Preclinical Models
- Building on the TRPM7 blocker NS8593, researchers created a set of 2-aminobenzimidazole analogues and identified two standout leads, SDUY212 and SDUY225, validated by electrophysiological recordings.
- Both compounds slowed growth, migration and invasion in MCF-7 and MDA-MB-231 breast cancer cells and triggered apoptosis and cell-cycle arrest; SDUY212 also shrank tumors in xenograft-bearing mice.
- The anti-invasive effect appeared linked to reduced EGF-triggered STAT3 activation downstream of TRPM7.
Actually running electrophysiology on the leads, not just IC50s from a fluorescence assay, is what makes me trust this series — ion channel hits die in droves from off-target and assay artifacts. Still, I'd want a TRPM6/TRPM8 selectivity panel before calling SDUY212 a real chemical probe; TRPM7 has essentially none, and the 2-aminobenzimidazole scaffold looks synthetically forgiving enough to actually chase that SAR.
New Benzimidazole-Tetrahydrofuran Series Delivers Potent, Selective NaV1.8 Inhibitor Lead for Pain
- NaV1.8 inhibition is a clinically validated non-opioid strategy for pain, with the marketed drug VX-548 (Journavx) serving as the benchmark; its metabolic pathways in humans and rats are well characterized.
- Researchers designed a new chemotype, 2-(2-benzimidazole)-substituted tetrahydrofurans, and applied structure-based optimization to circumvent VX-548's known metabolic liabilities while retaining nanomolar NaV1.8 potency and subtype selectivity.
- The resulting lead, compound 31, showed favorable oral bioavailability in rats, with plasma AUC more than 10-fold higher than VX-548, alongside potent in vivo analgesic efficacy.
- Pharmacokinetic behavior was consistent across species, with favorable profiles also seen in beagle dogs and cynomolgus monkeys.
- Compound 31 exhibited a favorable early safety profile, including no genotoxicity and weak hERG inhibition, supporting its status as a metabolically optimized preclinical lead for further evaluation.
Call this a metabolism play more than a new-target story. With VX-548's clearance liabilities already mapped in human and rat, swapping to a 2-benzimidazole-tetrahydrofuran scaffold reads as targeted scaffold-hopping around known soft spots rather than blind SAR exploration. That's the efficient way to run a fast-follower program: let the first approved drug's ADME data write your design brief. A >10x jump in rat AUC is the number that matters here — that's the difference between a compound needing frequent dosing with exposure gaps and one you can actually push into efficacy studies with margin. Clean hERG and no genotox flags this early derisks the biggest attrition risks before you've spent tox budget. The THF-benzimidazole core isn't exotic chemistry, nothing hard to scale — this looks like a real backup/second-gen candidate, not just a paper compound.
Novel Plant Metabolites Show Isoform-Selective Inhibition of Cav3.1 Calcium Channels
- Five new natural products, hyreptaones A-E (1-5), were isolated from the plant Hypericum reptans, defining a novel class of 1,2-seco-bicyclic polyprenylated acylphloroglucinols (BPAPs).
- Compounds 1-3 are the first 1,2-seco-BPAPs shown to derive from rare 3,3-diisoprenylated BPAP precursors, while 4 and 5 feature an unusual spirocyclic 6/5/5 ring system formed by further cyclization of the 1,2-seco-BPAP core.
- Structures were established using spectroscopic analysis together with X-ray crystallography.
- All five compounds preferentially inhibited the Cav3.1 T-type calcium channel over other T-type channel subtypes, indicating isoform selectivity.
- Compounds 4 and 5 additionally showed state-dependent modulation of Cav3.1 gating, marking them as a new class of Cav3.1 allosteric modulators.
Isoform selectivity within the T-type family (Cav3.1 vs 3.2/3.3) is exactly what's been missing from this space — most T-type blockers I've seen are promiscuous pore-blockers with narrow therapeutic windows, so five compounds hitting Cav3.1 preferentially is worth a second look. The state-dependent gating modulation in 4/5 is the more interesting story mechanistically: allosteric, conformation-selective action tends to buy better selectivity and fewer off-target liabilities than brute-force channel block. That said, I'm skeptical this scaffold is a med-chem starting point rather than a probe — a spirocyclic 6/5/5 BPAP that needed X-ray to nail down stereochemistry screams synthetic bottleneck, and five compounds isolated from one plant is not a supply chain, it's a bottleneck waiting to happen. I'd want SAR against simplified, truncated analogs before believing this is optimizable rather than just interesting.
FDA Slaps Partial Clinical Hold on Biohaven's Opakalim Days After $795M SK Biopharmaceuticals Licensing Deal
- On Aug 26, 2026, Biohaven granted SK Biopharmaceuticals global rights to its Kv7 ion-channel platform and lead candidate opakalim (BHV-7000/BHV-7043), a deal worth up to $795M — including $350M at closing (part of $400M in near-term cash), $150M in development/regulatory milestones, and tiered royalties on U.S. net sales.
- Opakalim is a selective Kv7.2/7.3 potassium-channel activator in Phase 2/3 development for focal epilepsy, with pivotal RISE-3 topline data expected in 2H 2026.
- On Sept 4, 2026, the FDA placed a partial clinical hold on the program after Biohaven flagged a metabolite observed in rodent studies whose relevance to humans is not yet established.
- The hold blocks new patient enrollment (mainly affecting RISE-2) but allows continued dosing of already-enrolled patients across the pivotal trials and open-label extension; RISE-3 is already fully enrolled.
- Biohaven says the RISE-3 readout timeline is not expected to change; the news still weighed heavily on Biohaven's stock.
Look at the cash waterfall before reading this as a disaster: SK already wired the firm money pre-hold, and Biohaven keeps it no matter what the FDA ultimately decides — the $395M in milestones and royalties was always the risk-bearing tranche, so SK's real downside exposure was deferred by deal structure, not dodged by luck. The sharper question is timing: a partial hold landing nine days after signature invites an obvious diligence question — was the rodent metabolite finding already in Biohaven's IND file when SK signed, or did SK simply outrun its own risk review? Practically, this is noise, not crisis: RISE-3 is fully enrolled, so the pivotal readout timeline is intact; only RISE-2's tail enrollment stalls. The bigger tail risk is reputational spillover to Kv7 as a mechanism class — that would sting Xenon's azetukalner more than it dents Biohaven's balance sheet.
Biohaven epilepsy drug suffers FDA hold days after attracting $350M deal ↗
Re-Engineering a Toxic HIV Inhibitor into a Safer Lead
- Starting from JK-4b, a potent but overly cytotoxic non-nucleoside reverse transcriptase inhibitor (NNRTI), researchers pursued structure-guided optimization to fix its safety liability.
- Design efforts targeted the NNRTI entrance channel, a sub-pocket near the classical allosteric site, to reshape how analogs bind reverse transcriptase and reduce off-target toxicity.
- Structure-activity relationship (SAR) studies across this new series pointed to compound 9n as the standout, with markedly improved selectivity and much lower cytotoxicity than JK-4b.
- Despite the safety redesign, 9n kept potent antiviral activity against both wild-type HIV-1 and clinically relevant drug-resistant variants, preserving the lead's core strength.
- The work illustrates entrance-channel-focused chemistry as a practical strategy for detoxifying promising but toxicity-limited NNRTI candidates.
This mechanism is what caught my eye: if cytotoxicity in JK-4b traced to deep induced-fit distortion in the classical pocket, moving the pharmacophore to a shallower, more solvent-exposed sub-pocket is a clean way to keep the RT H-bond network while shedding the strain that drives off-target hits. Retained potency against resistant variants is the real tell — K103N/Y181C-type mutations cluster in the classical pocket, so if 9n still works, its binding mode isn't leaning on that contact set, which also argues the toxicity really was off-target, not a right-target dose-limiting problem. Practically, a solvent-facing channel is easier SAR real estate — more room to tune logP/solubility without wrecking the core pharmacophore, so this reads generalizable, not a one-off rescue. Prefer this over the usual toxicity fixes (metabolite masking, prodrugging) — it's addressing binding geometry, not just downstream liability.