| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
PDE4D3 7.4 nM (IC50) PDE4D7 7.8 nM (IC50)
Zatolmilast targets phosphodiesterase 4D (PDE4D), a key enzyme in the cAMP signaling pathway that hydrolyzes cyclic AMP to AMP. The compound is a selective allosteric inhibitor of PDE4D. It selectively inhibits dimeric PDE4D isoforms that mimic the phosphorylated, activated forms of PDE4D. Zatolmilast has IC50 values of 7.8 nM for PDE4D7 and 7.4 nM for PDE4D3. It is less potent against wild-type dimeric PDE4D and monomeric PDE4D2 (IC50s of 1,018 nM, 2,013 nM, and 127 nM, respectively). By inhibiting PDE4D, the compound increases cAMP levels and promotes downstream signaling. |
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| ln Vitro |
Zatolmilast demonstrates potent in vitro inhibition of PDE4D with IC50 values of 7.8 nM for PDE4D7 and 7.4 nM for PDE4D3. It selectively inhibits dimeric PDE4D isoforms that mimic the phosphorylated, activated forms of the enzyme, with lower potency against wild-type dimeric PDE4D, dimeric PDE4DS133D, and monomeric PDE4D2 (IC50s of 1,018 nM, 2,013 nM, and 127 nM, respectively). The compound's allosteric mechanism of action provides selectivity and may reduce side effects compared to non-selective PDE4 inhibitors. These in vitro findings support its development for CNS disorders.
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| ln Vivo |
In the hippocampus, zatolmilast stimulates the production of brain-derived neurotrophic factor (BDNF), raises brain cAMP, and phosphorylates CREB[1]. At doses more than 0.3 mg/kg, zatolmilast (0.1–30 mg/kg; orally over 24 hours) improves mice's cognitive performance on novel object recognition (NOR)[2].
Zatolmilast has been evaluated in vivo in clinical trials. A Phase 2 randomized, double-blind, placebo-controlled, two-way crossover trial included 30 adult males with fragile X syndrome (FXS), demonstrating safety and positive results. Another Phase 2 study is planned for PPP2R5D neurodevelopmental disorder (Jordan's Syndrome). By selectively inhibiting PDE4D, Zatolmilast increases intracellular cAMP levels, which promotes a cascade of signaling events including BDNF. The compound is designed to enhance memory formation and potentially improve cognition. |
| Enzyme Assay |
The in vitro enzyme assay for Zatolmilast involves measuring its inhibition of PDE4D enzymatic activity. Recombinant human PDE4D isoforms (PDE4D7, PDE4D3, wild-type, and mutants) are expressed and purified. Enzyme activity is assessed by measuring the hydrolysis of cAMP to AMP using a scintillation proximity assay or fluorescence polarization. Zatolmilast is incubated with the enzyme and substrate at various concentrations. IC50 values are determined by fitting the inhibition data to a dose-response curve. The assay buffer typically contains Tris-HCl, MgCl2, and appropriate components for enzyme activity.
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| Cell Assay |
In vitro cellular assays for Zatolmilast typically use cell lines expressing PDE4D isoforms. Cells are treated with Zatolmilast at various concentrations. Intracellular cAMP levels are measured using ELISA or other cAMP detection assays. The compound's ability to increase cAMP levels is quantified. Additionally, downstream signaling markers such as CREB phosphorylation or BDNF expression can be assessed by Western blot or ELISA. These assays confirm the compound's cellular activity and support its use in CNS research.
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| Animal Protocol |
Animal/Disease Models: C57Bl6 mice[2]
Doses: 0.1, 0.3, 1, 3, 10, 30 mg/kg Route of Administration: po; 24 hrs (hours) Experimental Results: Dramatically improved novel object discrimination at doses above 0.3 mg/kg. Zatolmilast has been evaluated in vivo in clinical trials. A Phase 2 randomized, double-blind, placebo-controlled, two-way crossover trial included 30 adult males with fragile X syndrome (FXS). The primary endpoint of safety was demonstrated. Another Phase 2 randomized, double-blind, placebo-controlled study is planned for PPP2R5D neurodevelopmental disorder (Jordan's Syndrome). These clinical studies assess the compound's safety, tolerability, and efficacy in patients with neurodevelopmental disorders. |
| ADME/Pharmacokinetics |
Zatolmilast has been characterized in pharmacokinetic studies as part of its clinical development. The compound is orally bioavailable. Its chemical structure includes a trifluoromethyl group, which may influence its metabolic stability. Pharmacokinetic parameters such as Cmax, Tmax, half-life, and AUC have been determined in clinical trials. The compound's ability to cross the blood-brain barrier is important for its CNS indications. Further details on its PK profile are available in clinical study reports and publications.
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| Toxicity/Toxicokinetics |
Zatolmilast has been evaluated for safety in clinical trials. A Phase 2 trial in 30 adult males with fragile X syndrome demonstrated safety as the primary endpoint. The compound is generally well-tolerated. As a PDE4D inhibitor, Zatolmilast is designed to have a favorable safety profile compared to non-selective PDE4 inhibitors, which are associated with gastrointestinal side effects. Further toxicological data are available from preclinical studies and clinical trials. The compound is being developed for CNS disorders including FXS and Jordan's Syndrome.
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| References |
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| Additional Infomation |
BPN-14770 is being studied in clinical trial NCT02840279 (a multi-escalation study of BPN14770 in healthy young and older male or female subjects).
Zatolmilast (BPN14770) is a selective allosteric PDE4D inhibitor with IC50 values of 7.8 nM for PDE4D7 and 7.4 nM for PDE4D3. It is designed to enhance memory formation and improve cognition in CNS disorders. The compound has been evaluated in a Phase 2 clinical trial for fragile X syndrome (FXS), demonstrating safety, and is being studied for PPP2R5D neurodevelopmental disorder (Jordan's Syndrome). Zatolmilast increases intracellular cAMP levels and promotes BDNF signaling. It is an investigational drug with no regulatory approvals to date. |
| Molecular Formula |
C21H15CLF3NO2
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|---|---|
| Molecular Weight |
405.7975
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| Exact Mass |
405.074
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| CAS # |
1606974-33-7
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| PubChem CID |
90111638
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| Appearance |
White to off-white solid powder
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| LogP |
5.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
28
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| Complexity |
522
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=C([H])C([H])=C([H])C(=C1[H])C1C([H])=C(C([H])=C(C(F)(F)F)N=1)C([H])([H])C1C([H])=C([H])C(C([H])([H])C(=O)O[H])=C([H])C=1[H]
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| InChi Key |
LTSUMTMGJHPGFX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H15ClF3NO2/c22-17-3-1-2-16(12-17)18-9-15(10-19(26-18)21(23,24)25)8-13-4-6-14(7-5-13)11-20(27)28/h1-7,9-10,12H,8,11H2,(H,27,28)
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| Chemical Name |
2-[4-[[2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl]methyl]phenyl]acetic acid
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ≥ 100 mg/mL (246.43 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (5.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.17 mg/mL (5.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4643 mL | 12.3213 mL | 24.6427 mL | |
| 5 mM | 0.4929 mL | 2.4643 mL | 4.9285 mL | |
| 10 mM | 0.2464 mL | 1.2321 mL | 2.4643 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Link: https://clinicaltrials.gov/ct2/show/NCT07018492
Conditions:Hepatic ImpairmentLink: https://clinicaltrials.gov/ct2/show/NCT07012005
Conditions:Renal ImpairmentLink: https://clinicaltrials.gov/ct2/show/NCT05163808
Conditions:Fragile X Syndrome
Title:Study of Zatolmilast (BPN14770) in Participants With PPP2R5D Neurodevelopmental Disorder (Jordan's Syndrome JS)
Status:Active, not recruiting
updateDate:2026-01-20
Ctid:NCT06717438
Link: https://clinicaltrials.gov/ct2/show/NCT06717438
Conditions:Jordan's Syndrome|PPP2R5D Neurodevelopmental DisorderLink: https://clinicaltrials.gov/ct2/show/NCT07011992
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT03817684
Conditions:Alzheimer's DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT03569631
Conditions:Fragile X Syndrome|FXS|Fra(X) SyndromeLink: https://clinicaltrials.gov/ct2/show/NCT03861000
Conditions:DepressionLink: https://clinicaltrials.gov/ct2/show/NCT03030105
Conditions:Alzheimer DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT02648672
Conditions:Alzheimer's DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT02840279
Conditions:Alzheimer's DiseaseProducts are for research use only; We do not sell to patients
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