D-159404
D-159404 is an orally active, blood-brain barrier-permeable, selective allosteric PDE4D inhibitor. It partially inhibits cAMP hydrolysis by binding to the UCR2 regulatory domain, elevates intracellular cAMP levels, and triggers calcium influx, thereby improving working memory and episodic memory consolidation. D-159404 is used in research on asthma, chronic obstructive pulmonary disease, and cognitive impairment.
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- No. CAS: 1158221-32-9
- Fòrmula: C21H18ClFN2O2
- Peso molecular:384.84
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Almacenamiento:
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Descripciòn
IC50 & Target
[1]|
PDE4D |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| CHO | EC50 |
1415 nM
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Stimulation of concentration-dependent luminescence signals in PDE 4B1 CHO reporter cells (stably expressing human PDE 4B1, β1-adrenoceptor, cytosolic apoaequorin, and a cAMP-sensitive CNG channel) in the presence of 100 nM isoprenaline, measured via cAMP reporter assay with 10 min incubation prior to luminescence monitoring.
Stimulation of concentration-dependent luminescence signals in PDE 4B1 CHO reporter cells (stably expressing human PDE 4B1, β1-adrenoceptor, cytosolic apoaequorin, and a cAMP-sensitive CNG channel) in the presence of 100 nM isoprenaline, measured via cAMP reporter assay with 10 min incubation prior to luminescence monitoring.
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23987244 |
| CHO | EC50 |
157 nM
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Stimulation of concentration-dependent luminescence signals in PDE 4D3 CHO reporter cells (stably expressing human PDE 4D3, β1-adrenoceptor, cytosolic apoaequorin, and a cAMP-sensitive CNG channel) in the presence of 100 nM isoprenaline, measured via cAMP reporter assay with 10 min incubation prior to luminescence monitoring.
Stimulation of concentration-dependent luminescence signals in PDE 4D3 CHO reporter cells (stably expressing human PDE 4D3, β1-adrenoceptor, cytosolic apoaequorin, and a cAMP-sensitive CNG channel) in the presence of 100 nM isoprenaline, measured via cAMP reporter assay with 10 min incubation prior to luminescence monitoring.
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23987244 |
In Vitro
D-159404 (10 min) induces a potent concentration-dependent luminescent signal in PDE 4B1 CHO reporter cells in the presence of 100 nM Isoprenaline hydrochloride (HY-B0468), with a cellular EC50 of 1415 nM[1].
D-159404 (10 min) induces a potent concentration-dependent luminescent signal in PDE 4D3 CHO reporter cells in the presence of 100 nM Isoprenaline hydrochloride, with a cellular EC50 of 157 nM[1].
D-159404 potently inhibits recombinantly expressed full-length human PDE4D3, with an in vitro IC50 of 380 nM[1].
D-159404 exhibits a significantly reduced inhibitory potency against the recombinantly expressed truncated human PDE4D3 catalytic domain, with an in vitro IC50 of 20 μM[1].
D-159404 (20 min) increases the cAMP level in human HEK293 cells stimulated by Forskolin (HY-15371)[2].
D-159404 (15 min pre-incubation, 4 h total incubation) potently inhibits LTE4 production in human whole blood stimulated by Lichenase, Microorganism (HY-E70013), and its potency is greater than that observed in HEK293 cells[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
D-159404 (1-30 µg/kg; i.v.) enhances long-term memory consolidation in male ddY mice[2].
D-159404 (10-3000 µg/kg; i.v.) shows no activity in mouse models related to emetic behavior[2].
D-159404 (10 µg/kg; p.o.) exhibits oral activity, improves immediate spatial working memory in scopolamine-impaired male ddY mice, and enhances long-term memory consolidation in male ddY mice[2].
D-159404 (3-30 mg/kg; p.o.) improves scopolamine-induced cognitive impairment and enhances novel object recognition memory in mice[2].
D-159404 (1-1000 µg/kg; p.o.) improves novel object recognition memory in rats, with a minimum effective dose of 10 µg/kg[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:ddY mice (male, 30-35 g, scopolamine-induced cholinergic deficit)[2]
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Dosage:0.03 µg/kg; 0.1 µg/kg; 0.3 µg/kg
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Administration:i.v.
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Result:Reversed scopolamine-induced reduction in alternation behavior.
Restored alternation to levels similar to the unscopolaminated control (~60-70%) at doses of 0.1 µg/kg and 0.3 µg/kg.
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Animal Model:ddY mice (male, 30-35 g, long-term memory deficit)[2]
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Dosage:1 µg/kg; 3 µg/kg; 10 µg/kg; 30 µg/kg
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Administration:i.v.
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Result:Improved the discrimination index (a measure of novel object recognition).
Produced significant increases in discrimination index at doses ≥ 3 µg/kg.
Reached maximum discrimination index of ~0.25-0.3, similar to the reference compound rolipram.
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Animal Model:ddY mice (male, 24-32 g, dissociative anesthetic/alpha-2 adrenergic agonist-induced anesthesia)[2]
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Dosage:10 µg/kg; 30 µg/kg; 100 µg/kg; 300 µg/kg; 1000 µg/kg; 3000 µg/kg
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Administration:i.v.
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Result:Did not reduce the duration of dissociative anesthetic/alpha-2 adrenergic agonist-induced anesthesia.
Showed no activity even at doses up to 3000 µg/kg, which is 1000× the minimum effective dose for cognitive benefit in the novel object recognition test.
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Animal Model:ddY mice (male, 30-35 g, scopolamine-induced cholinergic deficit)[2]
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Dosage:10 µg/kg
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Administration:p.o.
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Result:Reversed scopolamine-induced cognitive impairment.
Demonstrated minimum effective dose consistent with its 28% oral bioavailability in mice.
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Animal Model:ddY mice (male, 30-35 g, long-term memory deficit)[2]
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Dosage:10 µg/kg
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Administration:p.o.
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Result:Improved the discrimination index in the novel object recognition test.
Demonstrated minimum effective dose consistent with its 28% oral bioavailability in mice.
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Animal Model:NMRI (adult male; scopolamine-induced cognitive impairment)[2]
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Dosage:3 mg/kg; 10 mg/kg; 30 mg/kg
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Administration:p.o.; single dose (90 minutes before testing)
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Result:Increased alternation behavior percentage to approximately 53% at 3 mg/kg.
Increased alternation behavior percentage to approximately 60% at 10 mg/kg.
Increased alternation behavior percentage to approximately 65% at 30 mg/kg.
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Animal Model:unspecified[2]
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Dosage:30 mg/kg; 100 mg/kg; 300 mg/kg; 1000 mg/kg
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Administration:p.o.; single dose (1 hour after first training session)
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Result:Increased discrimination index to approximately 0.12 at 100 mg/kg.
Increased discrimination index to approximately 0.19 at 300 mg/kg.
Increased discrimination index to approximately 0.19 at 1000 mg/kg.
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Animal Model:Wistar (adult; novel object recognition deficit)[2]
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Dosage:1 µg/kg; 10 µg/kg; 100 µg/kg; 1000 µg/kg
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Administration:p.o.; single dose (60 minutes before first training session)
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Result:Increased recognition index to approximately 75% at 10 µg/kg.
Increased recognition index to approximately 80% at 100 µg/kg.
Increased recognition index to approximately 75% at 1000 µg/kg.
Established minimum effective dose of 10 µg/kg.
Chemical Information
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No. CAS 1158221-32-9
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Peso molecular 384.84
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Fòrmula C21H18ClFN2O2
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SMILES
O=C(N)NC1=CC=C(C=C1)CC=2C=CC(OC)=C(C3=CC=CC(Cl)=C3)C2F
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[1]. Wunder F, et al. Characterization of the cellular activity of PDE 4 inhibitors using two novel PDE 4 reporter cell lines. Molecular pharmaceutics. 2013 Oct 07;10(10):3697-705. [Content Brief]
[3]. Ti H, et al. Targeted Treatments for Chronic Obstructive Pulmonary Disease (COPD) Using Low-Molecular-Weight Drugs (LMWDs). Journal of medicinal chemistry. 2019 Jul 11;62(13):5944-5978. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
D-159404 Related Classifications
HY-187591 Related Classifications
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