Dihexa
Dihexa is a research-only, angiotensin IV-derived oligopeptide studied preclinically as a proposed potentiator of HGF/c-Met signaling and synaptogenesis, with no human data and a key mechanistic paper retracted in 2025.
Dihexa (PNB-0408; N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide) is a small modified oligopeptide developed in the laboratory of Joseph Harding and colleagues at Washington State University as a metabolically stable, blood-brain-barrier-penetrant analog of angiotensin IV (AngIV). Structurally it is built around a Tyr-Ile core capped at the N-terminus with a hexanoyl group and terminated at the C-terminus as a 6-aminohexanoic amide, giving a molecular formula of C27H44N4O5 (CAS 1401708-83-5; PubChem CID 129010512).
In published preclinical work, Dihexa was reported to bind hepatocyte growth factor (HGF) with high affinity and to act as an allosteric potentiator of HGF signaling at its receptor tyrosine kinase, c-Met, with downstream effects described on dendritic spinogenesis and synaptogenesis. Rodent studies reported procognitive effects in models of impairment, including scopolamine-induced amnesia, aged animals, and the APP/PS1 transgenic Alzheimer's-type model (the latter via the PI3K/AKT pathway). The same chemical series later informed Athira Pharma's clinical-stage prodrug fosgonimeton (ATH-1017), which is converted in vivo to the active moiety designated ATH-1001; that program is a separate clinical effort and approval status does not transfer to Dihexa itself.
A critical caveat applies to the mechanism and early efficacy narrative: the foundational study connecting these peptides to HGF/c-Met activation (Benoist et al., "The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System," J Pharmacol Exp Ther 2014; 351(2):390-402; PMID 25187433) was retracted in April 2025 following a Washington State University research-integrity investigation that identified falsified data. The proposed mechanism should therefore be treated as unconfirmed.
Dihexa has never been tested in a published human clinical trial and is not an approved medicine in any jurisdiction. It is not FDA-approved (no IND or NDA on record) and is not authorised by the MHRA or EMA; it is sold only as a research chemical labelled "not for human consumption," with no GMP-grade pharmaceutical product available. Because its proposed action augments a growth-factor pathway (HGF/c-Met), commentators have raised theoretical proliferative/oncological concerns, but these are not characterised in controlled studies. Identity and purity of research-grade material are unverified.
Dihexa is an orally active, blood-brain-barrier-penetrant oligopeptide derived from angiotensin IV (the Nle1-AngIV analog lineage). In published preclinical work it was reported to bind hepatocyte growth factor (HGF) with high affinity and was described as an allosteric potentiator of HGF signaling at the receptor tyrosine kinase c-Met, with downstream effects reported on dendritic spinogenesis and synaptogenesis. Note that the foundational mechanistic study underpinning these claims (Benoist et al., J Pharmacol Exp Ther 2014) was retracted in 2025 for data-integrity concerns, so the mechanism should be regarded as proposed rather than firmly established.
- Human evidence
- Preclinical only (in vitro and rodent); no human clinical trials; key mechanistic paper retracted 2025
- Regulatory status
- Not an approved medicine in any jurisdiction. NOT FDA-approved (no IND/NDA on record) and not authorised by the MHRA or EMA. Sold only as a research chemical / "not for human consumption" reference compound; no GMP pharmaceutical product exists.
- Investigated in animal models as a probe of HGF/c-Met-dependent synaptogenesis and dendritic spine formation.
- Studied preclinically for cognitive/memory endpoints in rodent models of impairment (e.g. scopolamine amnesia, aged-rat and APP/PS1 Alzheimer's-type models).
- Used as a tool compound to explore angiotensin IV-derived peptide pharmacology and neurotrophic signaling pathways such as PI3K/AKT.
- No human clinical trial safety data exist; all reported findings derive from in vitro and rodent studies (e.g. PMC8615599).
- The principal mechanistic paper (Benoist et al., J Pharmacol Exp Ther 2014, PMC4201273) was retracted in April 2025 following a Washington State University research-integrity investigation, undercutting much of the early efficacy and mechanism narrative.
- Because its proposed action augments HGF/c-Met growth-factor signaling, theoretical proliferative/oncological concerns have been raised in commentary; these are unverified and not characterised in controlled studies.
- Not produced to pharmaceutical (GMP) standards; identity, purity and contaminants of research-grade material are unverified.
- [1]PubChem Compound: Dihexa (CID 129010512)PubChem
- [2]AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway (Brain Sci, 2021; preclinical)PMC / PubMed Central
- [3]RETRACTED: Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides via HGF/c-Met (Benoist et al., J Pharmacol Exp Ther 2014; 351:390-402; PMID 25187433; retracted Apr 2025)PMC / PubMed Central (retracted)
- [4]Retraction notice (J Pharmacol Exp Ther 2025; 392(4):103567; PMID 40312093)PubMed
- [5]Dihexa, CAS 1401708-83-5 (chemistry cross-check)Sigma-Aldrich