Dihexa
N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide, PNB-0408, angiotensin IV analogue, N-hexanoyl-Tyr-Ile-6-aminohexanamide
Dihexa is a small, lipid-capped dipeptide derivative of angiotensin IV, engineered at Washington State University for oral bioavailability and brain penetration. It was widely promoted on the claim that it potentiates hepatocyte growth factor signalling at its c-Met receptor to drive synaptogenesis. That mechanistic claim now rests substantially on papers that have been retracted, which changes how the whole compound should be read.
Mechanism
Dihexa was derived from angiotensin IV, a metabolite of angiotensin II with procognitive activity in rodents that is not explained by classical AT1 or AT2 receptors. The originating laboratory proposed that angiotensin IV analogues act as positive modulators of the hepatocyte growth factor (HGF) / c-Met receptor tyrosine kinase system in brain: dihexa was reported to bind HGF, promote its dimerisation, and thereby potentiate c-Met phosphorylation at HGF concentrations too low to activate the receptor alone. Downstream of c-Met sit PI3K/Akt and MAPK/ERK, both of which support dendritic spine formation and synaptogenesis, and the proposed effect was augmentation of existing HGF tone rather than de novo agonism. Structurally, capping the Tyr-Ile core with an N-terminal hexanoyl chain and a C-terminal aminohexanamide raises lipophilicity enough for oral absorption and blood-brain barrier transit while blocking aminopeptidase and carboxypeptidase degradation.
That account must now be read with serious reservations. Three papers from the originating group in the Journal of Pharmacology and Experimental Therapeutics were retracted in April 2025: the 2011 paper reporting that mimics of the HGF dimerisation domain exhibit anti-Met and anticancer activity, the 2012 paper establishing angiotensin IV analogues as HGF/Met modifiers, and the 2014 paper reporting that the procognitive and synaptogenic effects of these peptides depend on HGF/c-Met activation. The 2013 paper that first characterised dihexa itself carries an Expression of Concern, recorded in the Crossref update record as issued on 22 September 2021. The HGF/c-Met mechanism for dihexa is therefore not an established finding but a hypothesis whose principal supporting evidence has been withdrawn from the literature.
What the research shows
Taken at face value, the preclinical picture once looked strong: oral dihexa reversed scopolamine-induced cognitive deficits, improved performance in aged rats, and produced measurable increases in hippocampal spine density at doses far below those needed for angiotensin IV itself. Independent groups have reported activity in other systems: protection of lateral line hair cells from aminoglycoside damage in zebrafish, cognitive rescue in the APP/PS1 mouse via PI3K/Akt signalling, and effects in a 3-nitropropionic acid rat model of Huntington's-like pathology. A systematic review of angiotensin IV and angiotensin-(1-7) cognitive effects placed dihexa within a broader class with reproducible procognitive signals in animals.
But the retractions cut deep. The 2011, 2012 and 2014 JPET papers were the mechanistic backbone of the HGF/c-Met story, and the 2013 characterisation paper, the one that named dihexa and reported its antidementia activity in scopolamine and aged-rat models, sits under an Expression of Concern. When the foundational papers of a research programme are withdrawn, the appropriate response is not to discount everything downstream, but it is to stop treating the mechanism as settled and to weight independent replications much more heavily than the originating laboratory's own work. On that basis the honest summary is: dihexa is a brain-penetrant small molecule with some independently reported procognitive activity in rodents, an unresolved mechanism, and a compromised primary literature. There has never been a human trial of dihexa: no Phase 1, and a ClinicalTrials.gov search on 7 August 2026 returned no registered study of any kind.
Evidence assessment
Preclinical only
There is no human data of any kind, and the animal literature is compromised by the April 2025 retraction of three papers from the originating laboratory including the foundational HGF/c-Met mechanism papers, with an Expression of Concern on the primary dihexa characterisation study.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Retraction notice to 'The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System' Preclinical only
The paper reporting that the procognitive and synaptogenic effects of angiotensin IV-derived peptides depend on HGF/c-Met activation has been retracted; the retracted article is flagged as a Retracted Publication in PubMed.
Retraction notice to 'Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers' Preclinical only
The paper establishing angiotensin IV analogues as HGF/Met modifiers has been retracted.
Retraction notice to 'Mimics of the Dimerization Domain of Hepatocyte Growth Factor Exhibit Anti-Met and Anticancer Activity' Preclinical only
The third retracted paper in the series, covering anti-Met and anticancer activity of HGF dimerisation-domain mimics.
Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents Preclinical only
Reported that dihexa produced antidementia activity in scopolamine and aged-rat models with marked synaptogenic activity, the study that introduced and named the compound.
The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases Preclinical only
Sets out the design rationale and proposed HGF/c-Met mechanism for dihexa and related analogues.
AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway Preclinical only
Dihexa improved cognitive performance and memory with evidence of PI3K/Akt pathway involvement.
Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure Preclinical only
Dihexa protected hair cells from aminoglycoside-induced damage, in a non-cognitive system.
Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats Preclinical only
An angiotensin IV analogue reduced behavioural and pathological features in this model.
Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies Preclinical only
Found consistent procognitive signals for angiotensin IV and related analogues across animal studies, while noting the absence of human data.
Safety
There is no human safety data whatsoever: no Phase 1, no toxicology package in the public domain, no case series. This is not a compound with a thin safety record; it is a compound with no safety record. The theoretical concern most often raised is biologically serious and deserves stating plainly: c-Met is a proto-oncogene, and HGF/c-Met signalling drives proliferation, motility and invasion in a range of human cancers, which is why pharmaceutical development around this axis has focused overwhelmingly on c-Met inhibitors as anticancer agents. A compound designed to potentiate that pathway systemically, taken chronically by people with no monitoring, carries a plausible theoretical risk that no study has been done to characterise or exclude. The retraction of the papers claiming to establish the HGF/c-Met mechanism does not remove this concern. It simply means we now understand the compound's target biology even less well than we thought. It is worth noting that one of the three retracted papers was itself the group's anti-Met anticancer work, so the corner of the literature that spoke directly to the oncological question is exactly the corner that has been withdrawn.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation. Not a controlled drug, but as an unlicensed medicinal product it may not lawfully be sold, supplied or advertised for human use under the Human Medicines Regulations 2012. |
| United States | Not FDA-approved for any indication and never studied in a registered human trial. Dihexa has been among the substances raised in the context of FDA's review of bulk drug substances nominated for pharmacy compounding under section 503A; this monograph could not verify the compound's precise current placement on FDA's published 503A lists from primary FDA sources at the time of writing, and readers needing the authoritative position should consult those lists directly. In practice it is sold in the US only as an unapproved substance under a "research use only" label. |
| WADA (sport) | Not named individually on the WADA Prohibited List, but athletes should treat it as high-risk. Section S2.3 prohibits hepatocyte growth factor and, more broadly, other growth factors or growth factor modulators affecting muscle, tendon or ligament protein synthesis, vascularisation, regenerative capacity or fibre-type switching. A compound explicitly designed as an HGF/c-Met modulator is a plausible fit for that language. Category S0 would apply in any case as a non-approved substance. |
Questions
No. There is no Phase 1 study, no registered trial on ClinicalTrials.gov, and no published human exposure data of any kind. Everything known about dihexa comes from rodents, zebrafish and cell culture.
In April 2025 the Journal of Pharmacology and Experimental Therapeutics retracted three papers from the originating laboratory: the 2011 paper on HGF dimerisation-domain mimics, the 2012 paper establishing angiotensin IV analogues as HGF/Met modifiers, and the 2014 paper claiming the procognitive effects depend on HGF/c-Met. The 2013 paper that first characterised dihexa carries an Expression of Concern from September 2021. The proposed mechanism should now be treated as an open question, not a finding.
It is a legitimate theoretical concern that no surviving study has addressed. c-Met is a proto-oncogene and HGF/c-Met signalling promotes tumour growth and invasion, which is why most pharmaceutical work on this axis targets c-Met inhibition for cancer treatment. A compound intended to potentiate that pathway has never been assessed for oncological risk in any species over a meaningful timeframe, and the group's own anti-Met cancer paper is one of the three that were retracted.
Potency figures quoted online derive from cell-culture synaptogenesis comparisons in papers that have since been retracted or flagged. Even if the numbers were sound, in vitro potency in a dish says nothing about clinical benefit in a person, and no human has ever been studied taking it.