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BPN14770 (Zatolmilast)

Well Researched

First-in-class PDE4D negative allosteric modulator developed by Tetra Discovery Partners (Grand Rapids, MI) and acquired by Shionogi in…

Aliases (7)
Zatolmilast · BPN-14770 · BPN 14770 · D159797 · Tetra-779 · PDE4D NAM · PDE4D allosteric inhibitor
TYPICAL DOSE
PICASSO AD Phase 2: 10 or 25 mg twice daily (BI…
BID
ROUTE
Oral (tablet)
Oral
CYCLE
4-8 weeks on, 2-4 weeks off
As prescribed
STORAGE
Room temp; original container
Room temp

Overview

What is BPN14770 (Zatolmilast)?

BPN14770 (zatolmilast) is an investigational selective phosphodiesterase 4D (PDE4D) allosteric inhibitor in clinical trials for fragile X syndrome and developmental cognitive disorders. Designed to elevate cAMP signaling in the CNS without the classical PDE4 GI side effects.

Key Benefits

Improves cognitive function and language abilities in fragile X syndrome trials, supports synaptic plasticity, and may benefit Alzheimer's and other developmental cognitive impairments.

Mechanism of Action

Selective allosteric inhibitor of PDE4D — elevates cAMP and downstream PKA/CREB signaling, supporting synaptic plasticity and BDNF expression. Allosteric site avoids the emetic side-effect of classical PDE4 inhibitors.

▸Brand options7 known
ZatolmilastBPN-14770BPN 14770D159797Tetra-779PDE4D NAMPDE4D allosteric inhibitor

StatusNot scheduled (investigational drug; no approved indication anywhere as of 2026-05). Research-chem-only outside clinical trials.

Research Indications

Most Effective

The PDE4 family problem (why rolipram failed)

Phosphodiesterase 4 (PDE4) hydrolyzes cAMP — a critical second messenger downstream of dopamine D1, β-adrenergic, glucagon, serotonin 5-H…

Effective

What zatolmilast does differently

BPN14770 is a negative allosteric modulator (NAM) — it doesn't bind the catalytic site at all. It binds a regulatory region called UCR2 (…

Investigational

Downstream cascade (what raising cortical cAMP actually does)

1. PKA activation — protein kinase A unbinds from regulatory subunits when cAMP saturates them, freeing the catalytic subunit. 2. CREB ph…

Investigational

Plain English

BPN14770 is the "smart" version of the old memory-enhancing PDE4 inhibitor concept. Instead of jamming the enzyme's main switch (which ma…

Peptide Interactions

[cerebrolysin](cerebrolysin.md)
Synergistic

cerebrolysin provides exogenous neurotrophic input (BDNF/NGF mimetic peptides); BPN14770 raises endogenous BDNF transcription via cAMP/CREB. Mechanistically …

[nsi-189](nsi-189.md)
Synergistic

NSI-189 promotes hippocampal neurogenesis; BPN14770 enhances synaptic maturation/LTP via cAMP. Both target hippocampal plasticity by orthogonal mechanisms. T…

[nad-plus](nad-plus.md)
Synergistic

NAD+ precursors support sirtuin function (SIRT1 sits in the cAMP/SIRT1/Akt/Bcl-2 anti-apoptotic axis that BPN14770 engages preclinically). Substrate-level su…

[alcar](alcar.md)
Synergistic

ALCAR provides acetyl groups for hippocampal acetylcholine and supports mitochondrial function downstream of CREB-driven transcription. Theoretical substrate…

[semax](semax.md) / [n-acetyl-semax-amidate](n-acetyl-semax-amidate.md)
Synergistic

Russian peptides upregulate BDNF expression by an independent (non-PDE4D) mechanism. Theoretical additive BDNF stack.

[modafinil](modafinil.md)
Synergistic

orthogonal mechanism (orexin/histamine/DAT). No reported interaction. The combination would be "wakefulness state + memory consolidation substrate." If anyon…

[ibudilast](ibudilast.md)
Avoid

ibudilast is a non-selective PDE inhibitor (PDE3/4/10/11). Stacking with a PDE4D-selective inhibitor risks compounding cAMP elevation in the GI/area-postrema…

Rolipram, roflumilast, apremilast
Avoid

same class concern; redundant and cumulative emetic risk

High-dose theophylline, pentoxifylline
Avoid

non-selective PDE inhibitors, additive

Strong CYP3A4 inhibitors at high doses
Avoid

Phase 1 Japan study tested midazolam/donepezil interactions but specific results not public; treat ketoconazole/clarithromycin/strong inhibitors as caution-p…

Forskolin / coleus at supraphysiologic doses
Avoid

directly stimulates adenylyl cyclase, potentially adding to cAMP load. Theoretical; clinically unstudied.

Quality Indicators

✓

Pharmacy-dispensed, intact packaging

Prescription tablets in original sealed packaging from a licensed pharmacy.

!

Generic vs branded

Generics are usually fine but bioavailability can vary slightly; track if you switch.

✗

Unbranded blister or counterfeit risk

Counterfeit pharmaceuticals are a known issue; verify pharmacy and lot if buying internationally.

What to Expect

  • Onset
    No acute "kick." Effects, if any, build over days. Tmax in healthy volunteers ~1.5-3hr post-oral; half-life 10-12+ hours supports BID dosing.
  • Off-cycle
    No reported withdrawal or crash. Effects (subtle as they are) appear to fade over 1-2 weeks post-stop, consistent with the half-life.

Side Effects & Safety 6

Side Effects

  1. 1Headache — most common in Phase 1 elderly cohort across all dose groups; reduces or stabilizes with continued dosing in most users
  2. 2Vomiting/nausea — 10% (3/30) in FXS Phase 2 at 25mg BID; substantially less than rolipram's near-universal nausea, but not zero. More likely on empty stomach or with rapid dose escalation
  3. 3Mild GI — loose stools, dyspepsia (less specific signal)
  4. 4Mild fatigue — paradoxical, reported anecdotally
  5. 5Mild mood flattening at higher doses — consistent with inverted-U; resolves on dose reduction
  6. 6Insomnia if dosed late — uncommon at standard doses but possible given cAMP elevation; avoid dosing past ~5 PM

When to Stop

  • No cardiovascular signal in trials to date (older non-selective PDE4 inhibitors had QT concerns; allosteric PDE4D NAMs have not shown this)
  • No hepatotoxicity signal in PICASSO or FXS Phase 2 (n~285 combined)
  • No suicidality signal observed (relevant because some PDE4 inhibitor adjacent compounds have flagged this)
  • Long-term unknown — no human data beyond 12 weeks of continuous dosing in published trials. EXPERIENCE includes longer dosing and open-label extension; data not yet public.
  • First 2 weeks: GI tolerance window. If nausea persists past week 2, drop dose or stop.
  • Weeks 4-8: Cognitive-effect detection window. Track formally.
  • Indefinite: No long-term human safety dataset >12 weeks at therapeutic dose. Treat any chronic use as off-label and self-experimental.

References

Berry-Kravis et al. 2021 — Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial

nature.com · 2021

Nature Medicine; the foundational positive Phase 2 in FXS, n=30, 25mg BID

View Study

Berry-Kravis et al. 2021 — PubMed entry

pubmed.ncbi.nlm.nih.gov · 2021

same paper PubMed access

View Study

Zhang et al. 2018 — Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice

nature.com · 2018

Neuropsychopharmacology; the foundational pharmacology paper

View Study

Zhang et al. 2018 — PMC version

pmc.ncbi.nlm.nih.gov · 2018

full text

View Study

BPN14770 — ALZFORUM therapeutics database

alzforum.org · 2021

comprehensive trial history through 2021 including PICASSO Alzheimer's details

View Study
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