Dihexa acetate: FDA and NCATS identity records standardize the active moiety as DIHEXA with UNII 9WYX65A5C2, CAS 1401708-83-5, molecular formula C27H44N4O5, and molecular weight about 504.66 g/mol.

Overview

Dihexa remains investigational. The strongest defensible facts are chemical identity and preclinical activity, not human efficacy. NCATS lists dihexa as Investigational, and FDA's UNII service explicitly notes that UNII availability does not imply regulatory review or approval.

The best-supported efficacy signal is preclinical. Publicly accessible sources describe improved Morris water maze performance in scopolamine-impaired rats and aged rats, plus increased dendritic spine density and synaptogenesis in hippocampal neurons. Effective preclinical routes included intracerebroventricular, oral, intraperitoneal, and intravenous dosing, but no published human efficacy studies for dihexa itself were identified.

Market language often collapses dihexa, "dihexa acetate," and the later phosphate prodrug fosgonimeton into one bucket, but that is not supportable. NCATS specifically links fosgonimeton as a prodrug with dihexa as an active metabolite, meaning they are related but not interchangeable substances.

Safety is the major unresolved liability: no long-term animal or human safety literature was identified, rodent half-life appears unusually long, and HGF/c-MET pathway activation raises theoretical concerns regarding tumorigenesis and cancer progression. Acute, chronic, genotoxicity, reproductive toxicity, and formal drug–drug interaction datasets are unspecified.

Human clinical-development relevance lies with fosgonimeton, not dihexa. Athira/ACT-AD materials linked from public records identify an Alzheimer's disease study at NCT04491006, and Reuters reported in 2024 that the 312-patient, 26-week, once-daily-injection trial failed its primary efficacy goal. That does not create clinical proof for dihexa itself, but it matters because many commercial narratives borrow credibility from the prodrug program.

What it is

Dihexa is a N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, an angiotensin IV–derived compound. FDA's UNII record lists synonyms including PNB-0408, ATH-1001, and N-(1-oxohexyl)-L-tyrosyl-N-(6-amino-6-oxohexyl)-L-isoleucinamide. NCATS records the same substance as dihexa and identifies fosgonimeton as its prodrug relationship.

Attribute	Verified value
Preferred substance name	DIHEXA
IUPAC name	6-[(2S,3S)-2-[(2S)-2-hexanamido-3-(4-hydroxyphenyl)propanamido]-3-methylpentanamido]hexanamide
Common alias	N-hexanoic-Tyr-Ile-(6) aminohexanoic amide
Development codes	PNB-0408; ATH-1001
CAS	1401708-83-5
UNII	9WYX65A5C2
Molecular formula	C27H44N4O5
Molecular weight	504.6621–504.672 g/mol
InChIKey	XEUVNVNAVKZSPT-JTJYXVOQSA-N
Stereochemistry	Absolute; 3 defined stereocenters of 3 possible

Common forms in circulation

Dihexa free base is the authoritative active-moiety record; "dihexa acetate" is an unverified salt presentation in the reviewed authoritative databases; fosgonimeton is a distinct phosphate prodrug with its own chemical record. These forms should not be collapsed into one undifferentiated "dihexa" product family.

How it's proposed to work

The current mechanistic anchor is that dihexa is a small HGF/MET-system modulator derived from angiotensin IV. Increased c-Met phosphorylation in adult rat hippocampal slices at effective concentrations shows synergy with sub-threshold HGF, and dihexa binds HGF with high affinity; HGF antagonism blocks its cognitive and spinogenic effects.

A crucial nuance is that the same patent family also contains related 6-AH analogs with antagonist behavior, including HGF dimerization blockade and inhibition of HGF-dependent scattering in non-dihexa family members. For dihexa itself, the later and more directly relevant narrative is positive modulation/pro-neurotrophic activity.

Purported benefits, by evidence strength

Purported benefit	Evidence strength	What the evidence supports	What it does not support
Improved cognition in impaired rodent models	Preclinical	Reversal or mitigation of water maze deficits in scopolamine-impaired rats and benefit signal in aged rats.	Human efficacy; Alzheimer's disease treatment claims.
Increased dendritic spines / synapses	Preclinical	Roughly threefold increase in spine density and functional synapse formation in hippocampal neuronal culture under experimental conditions.	Durable benefit in humans; global neuroregeneration claims.
BBB penetration and oral activity	Preclinical	Rodent BBB penetrance and oral activity were reported in preclinical work.	Human oral bioavailability; human CNS exposure.
Positive modulation of HGF/MET signaling	Mechanistic / preclinical	c-Met phosphorylation and HGF-dependent mechanistic linkage in slices and neuronal systems.	Fully characterized receptor pharmacology or numeric binding-affinity certainty for dihexa itself.
Neuroprotective / otoprotective effects	Early preclinical	A related publication line reported protection of lateral-line hair cells from aminoglycoside exposure.	Human otoprotection.
Alzheimer's treatment in humans	Not supported	Unspecified for dihexa in humans.	Any claim of clinical proof.
Anti-aging / longevity / human nootropic use	Not supported	Mechanistic plausibility only, not clinical proof.	Any marketed anti-aging or smart-drug efficacy claim.

Key preclinical studies

Study or source	Type	Dose / route	Main endpoints	Key findings
McCoy-era dihexa package summarized in ADDF and patent	Rodent efficacy / PK	ICV up to 1 nmol; oral up to 2 mg/kg/day; IV up to 10 mg/kg; IP up to 20 mg/kg.	Morris water maze, probe trial, PK	Oral and ICV dihexa improved water-maze performance; high oral dose became indistinguishable from untreated controls in the scopolamine model. Rat serum half-life about 330–335 min.
Hippocampal spinogenesis work summarized in ADDF/patent	Cell / ex vivo	Often 10⁻¹² M in neuronal systems; 30-min or 5-day exposures depending on assay.	Spine density, synaptic markers, mEPSCs, phospho-Met	Nearly threefold increase in spine density; synapses appeared functional; c-Met phosphorylation increased under active conditions.
Benoist et al. line summarized in ADDF	Mechanistic	Oral dihexa plus antagonist blockade paradigm	Morris water maze, spinogenesis	HGF antagonist blocked procognitive and spine effects, supporting HGF/c-MET dependence.
Uribe et al. 2015	Preclinical translational	Unspecified	Hair-cell survival	Reported otoprotective signal in a non-dementia sensory model.
Siller et al. 2015	Human cell differentiation model	100 nM for 10 days in maturation phase.	Hepatocyte-like differentiation	Demonstrates pathway utility in stem-cell differentiation, not therapeutic efficacy.

Clinical data

For dihexa itself, no human studies have been published and no same-molecule efficacy trials were identified. The closest human-development evidence is the related fosgonimeton program, which is chemically distinct and should not be treated as interchangeable with dihexa.

Regulatory status

Dihexa is an investigational substance, not an approved drug product. NCATS labels dihexa Investigational, while FDA's UNII service cautions that UNII assignment does not imply approval.

Region	Verified status in public sources	Notes
United States	Investigational; no approval year identified.	FDA UNII exists for identity only; this is not approval.
European Union	Unspecified	No verified regulator record was identified.
United Kingdom	Unspecified	No verified regulator record was identified.
Canada	Unspecified	No verified regulator record was identified.
Australia	Unspecified	No verified regulator record was identified.

No controlled-drug scheduling or special legal-control designation for dihexa was verified in the reviewed public source set. That should be understood as unspecified, not as an affirmative claim that the substance is freely legal in every jurisdiction.

Safety

No publications documenting long-term safety in animals or humans were identified, and the mechanism raises a theoretical concern that HGF/c-MET activation could facilitate tumorigenesis or cancer progression. No public chronic toxicology package, carcinogenicity battery, genotoxicity package, reproductive toxicity package, or human adverse-event dataset for dihexa itself was identified.

Domain	Publicly verifiable status
Acute toxicity	Limited / not systematically characterized.
Chronic toxicity	Unspecified; no long-term publications identified.
Genotoxicity	Unspecified
Reproductive toxicity	Unspecified
Carcinogenicity / tumor promotion	Mechanism raises theoretical concern.
Special populations	Unspecified

Pharmacokinetics

Parameter	Status
Absorption	Oral activity shown preclinically; human absorption unspecified.
Distribution	BBB penetration reported in rodents; human CNS exposure unspecified.
Metabolism	Human metabolism unspecified.
Elimination	Rat serum half-life about 330–335.5 min; in vivo rat half-life reported as 12.68 days IV and 8.83 days IP.
Primary target/pathway	HGF/c-MET system; exact numeric binding affinity for dihexa itself unspecified in accessible reviewed sources.

Publicly accessible interaction studies for dihexa were not identified; drug interactions have not been formally studied.

Public preclinical work used powder stock stored frozen, then DMSO-based solutions with dilution into water or 50% DMSO. Rodent administration routes included oral gavage, ICV, IV, and IP. The related prodrug fosgonimeton reached human testing as a once-daily injectable regimen.

ADDF stated in 2021 that dihexa was not commercially available in the U.S., although private clinical administration was mentioned. Current public identity sources still present the substance as investigational rather than an approved or routinely distributed pharmaceutical product.

References

FDA UNII Search Service. DIHEXA — UNII 9WYX65A5C2. U.S. Food and Drug Administration identity record.
NCATS Inxight Drugs. DIHEXA — investigational substance record, identifiers, and relationship to fosgonimeton as prodrug/active metabolite.
Harding JW, Wright JW, Benoist CC, Kawas LH, Wayman GA. US8598118B2 — Hepatocyte growth factor mimics as therapeutic agents. Google Patents / patent text record, issued 2013.
Alzheimer's Drug Discovery Foundation. Dihexa — Cognitive Vitality Report. Updated August 13, 2021.
Reuters. Athira Pharma's Alzheimer's drug fails in mid-to-late stage trial. September 2024.
Wright JW, Harding JW. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease. Journal of Alzheimer's Disease. 2015.
Benoist CC, Wright JW, Zhu M, Appleyard SM, Wayman GA, Harding JW. Facilitation of hippocampal synaptogenesis and spatial memory by C-terminal truncated Nle1-angiotensin IV analogs. Journal of Pharmacology and Experimental Therapeutics. 2011.
Uribe PM, Kawas LH, Harding JW, Coffin AB. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure. Frontiers in Cellular Neuroscience. 2015.
Siller R, Greenhough S, Naumovska E, Sullivan GJ. Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells. Stem Cell Reports. 2015.
Johnston JL, Reda SM, Setti SE, et al. Fosgonimeton, a Novel Positive Modulator of the HGF/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia. Neurotherapeutics. 2023.
Reda SM, Setti SE, Berthiaume AA, et al. Fosgonimeton attenuates amyloid-beta toxicity in preclinical models of Alzheimer's disease. Neurotherapeutics. 2024.

Dihexa acetate