Dihexa

What it is

Dihexa is a metabolically stabilized, orally bioavailable peptidomimetic derived from the N-terminal tripeptide (Nle-Tyr-Ile) of norleucine1-angiotensin IV, an analog of the endogenous hexapeptide angiotensin IV (AngIV: VYIHPF). Earlier AngIV analogs with procognitive properties were limited by rapid metabolic degradation and poor blood-brain barrier (BBB) permeability; Dihexa was chemically engineered to overcome both barriers, yielding an orally active compound that crosses the BBB (PMID 23055539, PMID 25455861). The primary mechanism is activation of the hepatocyte growth factor (HGF) / c-Met receptor system in the central nervous system. Dihexa binds with high affinity to HGF and potentiates its activation of the c-Met receptor. This HGF/c-Met signaling drives synaptogenesis, neurogenesis, and neuroprotection; synaptogenic effects were abolished by the selective c-Met inhibitor PHA-665752, confirming mechanism-dependence. Downstream, c-Met receptor activation stimulates mitogenesis, morphogenesis, stem cell differentiation, and neurogenesis across multiple cell types. In APP/PS1 Alzheimer's model mice, Dihexa additionally activates the PI3K/AKT signaling pathway. A 2018 systematic review of 32 animal studies confirmed that AngIV and its analogs — the class that includes Dihexa — produce consistent procognitive effects across rodent models of memory and learning, with efficacy seen in both normal animals and models of cognitive impairment. As of the reviewed literature, all mechanistic and efficacy data are preclinical; no human pharmacokinetic, pharmacodynamic, or efficacy data have been published.

Class: Peptidomimetic / Angiotensin IV analog / HGF/c-Met receptor system activator

What it's studied for

• Cognitive impairment and Alzheimer's disease model Animal studies only
  • APP/PS1 Alzheimer's model mice treated with Dihexa at multiple oral doses showed restored spatial learning and cognitive function in the Morris water maze; Dihexa-treated animals had increased neuronal cell counts on Nissl staining, elevated SYP (synaptophysin) protein expression, and decreased amyloid-beta plaque load PMID 34827486 Sun X et al. Brain Sci. 2021.
  • Dihexa and parent compound Nle1-AngIV demonstrated procognitive and synaptogenic effects in rodents. Dihexa bound hepatocyte growth factor (HGF) with high affinity and potentiated c-Met receptor activation; synaptogenic effects were completely blocked by the c-Met inhibitor PHA-665752, confirming HGF/c-Met pathway depe PMID 25187433 Benoist CC et al. J Pharmacol Exp Ther. 2014.
  • Systematic review of 32 animal studies on AngIV and Ang-(1-7) cognitive effects. 7/11 normal-animal studies found AngIV beneficial on passive avoidance, conditioned avoidance, and object recognition tasks. 8/9 cognitive-impairment model studies found salutary effects of AngIV and its analogs (including Nle1-AngIV, the PMID 29733881 Ho JK et al. Neurosci Biobehav Rev. 2018.
• Parkinson's disease and neurodegenerative disease Animal studies only
  • Review of the development of small-molecule AngIV analogs for Alzheimer's and Parkinson's disease. Documents the pharmacological rationale for Dihexa's design and summarizes preclinical evidence for AngIV analogs in dopaminergic and cholinergic models. Concludes that Dihexa and related analogs represent a novel drug de PMID 25455861 Wright JW et al. Prog Neurobiol. 2015.
• Huntington's disease model Animal studies only
  • Dihexa (PNB-0408) administered to rats with 3-nitropropionic acid (3-NP)-induced Huntington's disease-like symptoms attenuated motor and cognitive impairment compared to vehicle controls. Authors cite Dihexa's prior success in Alzheimer's and Parkinson's animal models as the rationale. Specific dose, route, and sample PMID 38489193 Wells RG et al. J Huntington's Dis. 2024.

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.

Safety signals

• No adverse events described in the APP/PS1 mouse study abstract at any tested dose of Dihexa. Absence of reported events in this single animal study does not establish safety in humans. PMID 34827486
• No human safety or tolerability data exists. No Phase I trial has been published in any reviewed abstract. All safety inference is from rodent models only. PMID 25455861

Contraindications

• No formal contraindications established in reviewed literature. Compound has not been evaluated in human clinical trials. Individuals on medications affecting the renin-angiotensin system (ACE inhibitors, ARBs) should consult a physician before use, given Dihexa's derivation from the angiotensin system. PMID 25649658