Danegaptide
A connexin-43 gap junction modifier, from heart attack to diabetic eye disease
Danegaptide (ZP1609) is an oral dipeptide analogue of rotigaptide that modifies connexin-43, the protein that forms gap junctions linking neighbouring cells. It reduced infarct size in pigs, but a 585-patient phase 2 trial in heart attack found no benefit. It has since been tested in diabetic retinopathy, where a 24-patient phase 1b study in 2026 found no serious drug-related adverse events.
What is it?
Gap junctions are channels built from connexin proteins that let neighbouring cells share ions and small molecules. In the heart, connexin-43 keeps muscle cells electrically coupled; in the brain it links astrocytes; and half-channels, or hemichannels, can leak ATP from injured cells. Danegaptide was developed as a small, orally available relative of rotigaptide, an antiarrhythmic peptide targeting connexin-43.
The animal results were encouraging. Given ten minutes before reperfusion in pigs after an hour of coronary occlusion, it cut infarct size from 46% to 25% of the area at risk, as much as ischaemic postconditioning. In mice it crossed the blood-brain barrier, increased astrocyte coupling and reduced infarct volume after stroke. In human kidney cells it blocked hemichannel ATP release and protected against TGF-beta1 injury. But in pigs with kidney ischaemia it did not improve kidney function at two weeks.
The heart attack trial gave the clearest answer. Patients with STEMI undergoing primary angioplasty were randomised to high-dose or low-dose danegaptide or placebo; 585 were enrolled and about 80 per group had evaluable cardiac MRI at three months. Myocardial salvage, final infarct size and ejection fraction did not differ, nor did clinical outcomes.
In 2026 a Dublin group reported that danegaptide improved the blood-retina barrier in animal models and countered VEGF-driven leakage in human retinal cells, partly through the protein TNFSF15. In an early phase 1b trial of oral danegaptide in 24 patients with nonproliferative diabetic retinopathy and mild macular oedema, there were no serious drug-related adverse events. Whether it helps vision is untested.
At a Glance
Every value in this table is printed from the Grey Peptides dataset, the same record the compound explorer and comparison tool read, so the three can never disagree.
Published Research
Studies of danegaptide, from their PubMed abstracts.
Phase 2 in STEMI
Of 585 randomised patients, per-protocol MRI showed no difference in myocardial salvage index (63.9, 65.6 and 66.7 for high dose, low dose and placebo; P = 0.40), infarct size or ejection fraction, and no difference in clinical outcome.
Diabetic retinopathy: preclinical and phase 1b
Danegaptide improved inner blood-retina barrier function via connexin-43 and by functionally antagonising VEGF; in a phase 1b trial in 24 patients with NPDR and mild centre-involved macular oedema, no serious adverse events related to oral danegaptide were found.
Infarct size in pigs
Given 10 minutes before reperfusion after 60 minutes of coronary occlusion, ZP1609 reduced infarct size to 25% of the area at risk versus 46% with immediate reperfusion, similar to ischaemic postconditioning (31%).
Stroke in mice
Danegaptide increased astrocytic connexin-43 coupling without affecting hemichannels, reached brain tissue within an hour of reperfusion, and significantly reduced infarct volume.
Kidney ischaemia in pigs
In 20 pigs with unilateral renal ischaemia-reperfusion, danegaptide infusion did not change GFR immediately or at 14 days, urinary NGAL or renal blood flow.
Human kidney tubule cells
Danegaptide blocked connexin-43 hemichannel ATP release in primary human proximal tubule cells, reduced paracellular permeability and inhibited TGF-beta1-induced cytokine changes.
Side Effects & Contraindications
Reported Side Effects
From the trials above.
Contraindications & Cautions
There is no label.
Legal Status
Danegaptide is investigational.
Frequently Asked Questions
?What is danegaptide?
An investigational oral dipeptide, related to rotigaptide, that modifies connexin-43 gap junctions, the channels that couple neighbouring heart, brain and other cells.
?Did danegaptide work in heart attacks?
No. It shrank infarcts in pigs, but a phase 2 trial with 585 STEMI patients found no difference in salvaged heart muscle, infarct size, ejection fraction or outcomes.
?Why is it being tested in diabetic retinopathy?
In animals and human retinal cells it tightened the blood-retina barrier and countered VEGF-driven leakage, and it can be taken by mouth instead of injected into the eye. A 24-patient phase 1b found no serious drug-related adverse events; efficacy is untested.
References
- [other] PubChem CID 16656685, Danegaptide: formula C14H17N3O4, molecular weight 291.30. Read October 3, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/16656685
- [fda] FDA. Drugs@FDA (openFDA): no application on record for danegaptide. Read October 3, 2026.
- [registry] ClinicalTrials.gov API v2, read October 3, 2026: NCT01977755 (phase 2 cardioprotection proof-of-concept in STEMI, 591 registered, completed).
- [clinical-trial] Engstrøm T, et al. "Danegaptide for primary percutaneous coronary intervention in acute myocardial infarction patients: a phase 2 randomised clinical trial." Heart, 2018;104(19):1593-1599. PMID: 29602883.
- [pubmed] Hudson N, et al. "Preclinical and clinical evaluation of systemic danegaptide for the treatment of nonproliferative diabetic retinopathy." Sci Transl Med, 2026;18(868):eaed8692. PMID: 42777083.
- [pubmed] Skyschally A, et al. "The antiarrhythmic dipeptide ZP1609 (danegaptide) when given at reperfusion reduces myocardial infarct size in pigs." Naunyn Schmiedebergs Arch Pharmacol, 2013;386(5):383-91. PMID: 23397587.
- [pubmed] Freitas-Andrade M, et al. "Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice." Biomolecules, 2020;10(3). PMID: 32110860.
- [pubmed] Amdisen C, et al. "Testing Danegaptide Effects on Kidney Function after Ischemia/Reperfusion Injury in a New Porcine Two Week Model." PLoS One, 2016;11(10):e0164109. PMID: 27760220.
- [pubmed] Squires PE, et al. "Danegaptide Prevents TGFβ1-Induced Damage in Human Proximal Tubule Epithelial Cells of the Kidney." Int J Mol Sci, 2021;22(6). PMID: 33802083.
Sources & Citations
Studies were read from their PubMed records and trial registrations from ClinicalTrials.gov, October 3, 2026.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Consult a licensed healthcare provider before making health decisions.