BPN14770
Subtype-selective PDE4D allosteric inhibitor that raises cAMP/BDNF, with phase 2 human data.
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Pharmacology
Contents
WHAT IS BPN14770?
Detailed overview
BPN14770 (also known as zatolmilast) is a brain-penetrant, subtype-selective allosteric inhibitor of phosphodiesterase-4D (PDE4D), originally developed by Tetra Discovery Partners (later Shionogi) for memory and cognitive indications. Rather than fully switching the enzyme off, it partially and allosterically inhibits PDE4D, which slows the breakdown of cyclic AMP (cAMP) in neurons, strengthens PKA and CREB signaling, and increases the memory-linked expression of BDNF. The partial, allosteric mode is designed to reduce the nausea and vomiting typical of classic PDE4 inhibitors such as rolipram. In a 2021 phase 2 randomized, placebo-controlled trial (Berry-Kravis et al., Nature Medicine), adult men with fragile X syndrome showed improvement on cognitive and language endpoints. The compound remains an investigational drug and has not received marketing approval.
Mechanism
Subtype-selective PDE4D allosteric inhibitor (raises cAMP/CREB/BDNF)
Evidence
Phase 2 human RCT (fragile X) + preclinical memory data
Legal status
Investigational drug (not approved)
Receptor profile
- PDE4D phosphodiesteraseStrong
- cAMP / PKA / CREB signalingModerate
- BDNF expressionModerate
Safety
Side effects, stop signs, contraindications
Side effects · 5
- Headache, typical of the PDE4 inhibitor class
- Nausea and gastrointestinal upset (milder than older PDE4 inhibitors, as the molecule targets the PDE4D subtype selectively)
- Vomiting at higher doses
- Dizziness and fatigue reported in clinical trials
- Long-term safety not established: only limited phase 2 human data exist
Contraindications · 4
- Pregnancy and breastfeeding: safety not established, avoid
- Unapproved investigational drug; not recommended outside a clinical trial
- Known PDE4 inhibitor intolerance or a strong tendency to nausea
- Additive gastrointestinal side effects possible with other GI-irritant agents
Related Nootropics
Same therapeutic category
Studies
Related research and clinical findings
Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial
Berry-Kravis EM, Harnett MD, Reines SA, Reese MA, Ethridge LE, Outterson AH, Michalak C, Furman J, Gurney ME
Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice
Zhang C, Xu Y, Zhang HT, Gurney ME, O'Donnell JM
Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D)
Gurney ME, Cogram P, Deacon RM, Rex C, Tranfaglia M
Protection from Amyloid β Peptide-Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor
Cui SY, Yang MX, Zhang YH, Zheng V, Zhang HT, Gurney ME, Xu Y, O'Donnell JM
Effects of chronic inhibition of phosphodiesterase-4D on behavior and regional rates of cerebral protein synthesis in a mouse model of fragile X syndrome
Rosenheck M, Sheeler C, Saré RM, Gurney ME, Smith CB
FAQ
FAQ
Subtype-selective PDE4D allosteric inhibitor that raises cAMP/BDNF, with phase 2 human data.
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Structure & chemistry
The information here is strictly for educational and scientific purposes. It does not replace medical advice or clinical consultation, and it does not encourage illegal substance or pharmaceutical use. Data is sourced. When in doubt, consult your doctor.