| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
Sipagladenant specifically targets the adenosine A2A receptor, a G-protein-coupled receptor (GPCR) highly expressed in the basal ganglia of the brain. It acts as a potent inverse agonist (pKI = 9.93 for the human A2A receptor), meaning it binds to the receptor and stabilizes it in an inactive conformation, reducing its constitutive activity. By blocking A2A receptors, Sipagladenant disinhibits dopaminergic signaling, thereby improving motor function and cognitive performance.
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| ln Vitro |
In vitro, Sipagladenant demonstrates potent and selective binding to the human A2A receptor with a pKI value of 9.93. It exhibits a distinct 'insurmountable' antagonism, which is characterized by a reduction in the maximal response of an agonist (e.g., CGS21680) without a parallel rightward shift of the concentration-response curve, indicating it acts as an allosteric or non-competitive antagonist. It has low affinity for other neurotransmitter receptors, ensuring a high degree of selectivity.
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| ln Vivo |
Sipagladenant (oral; 0.3 mg/kg; once) therapy improves cognitive impairment caused by decreased dopamine function in the medial prefrontal cortex [2]. Treatment with cisparadenam (oral; 0.1 mg/kg; once) improves alternating behavior [2]. Treatment with cisparadenam (oral; 0.1 mg/kg; once) improves gait metrics [2].
In vivo, Sipagladenant has shown efficacy in preclinical models of frontal lobe dysfunction. At an oral dosage of 0.3 mg/kg, it significantly improves cognitive impairment associated with reduced dopamine function in the medial prefrontal cortex. It is also effective in reversing motor deficits in rodent models of Parkinson's disease. Its ability to cross the blood-brain barrier is essential for its CNS activity. It has a favorable brain-to-plasma ratio for CNS penetration. |
| Enzyme Assay |
For in vitro binding assays, standard radioligand binding protocols are used. Human A2A receptor-expressing CHO cell membranes are incubated with [3H]-SCH 58261 (a selective A2A antagonist) in the presence or absence of increasing concentrations of Sipagladenant (0.01 nM - 10 microM). The reaction is carried out in 50 mM Tris-HCl buffer (pH 7.4) at 25degC for 60 minutes. Bound radioactivity is separated by rapid filtration and counted. Ki values are calculated from competition curves using the Cheng-Prusoff equation.
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| Cell Assay |
For in vitro cell assays, CHO-K1 cells stably expressing the human A2A receptor are seeded in 96-well plates. Sipagladenant is added at various concentrations (0.1 nM - 10 microM) and incubated for 30 minutes. The A2A receptor is then activated with an agonist like CGS21680 (100 nM). The intracellular cAMP level is measured using a homogeneous time-resolved fluorescence (HTRF) cAMP assay kit. The IC50 for inhibition of agonist-stimulated cAMP production is calculated.
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| Animal Protocol |
Animal/Disease Models: Medial prefrontal lobe dopaminergic terminal damage CD (SD) IGS male rat [2]
Doses: 0.3 mg/kg Route of Administration: Oral; Route of Administration: Oral. 0.3 mg/kg; primary Experimental Results: demonstrated longer exploration time for novel objects (65.03%) than for familiar objects (34.97%) (p<0.001). Animal/Disease Models: Cognitive impairment and/or movement disorder ICR mice [2] Doses: 0.1 mg/kg Route of Administration: Oral; 0.1 mg/kg; Experimental Results: Compared with the excipient administration group (59.6%), demonstrated Dramatically higher alternation behavior (69.5%) (p<0.01). Animal/Disease Models: Cognitive impairment and/or movement impairment ICR mice [2] Doses: 0.1 mg/kg Route of Administration: Oral; 0.1 mg/kg; Experimental Results: Compared with the vehicle administration group, the maximum left hind paw The contact area and gait area increased Dramatically (p<0.05), and the maximum contact area and gait area of the right front paw tended to become larger (p<0.1). For in vivo animal models, the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease is used. Rats are unilaterally injected with 6-OHDA to induce a dopamine-depleted striatum. Sipagladenant is administered orally (0.1-3 mg/kg). Motor function is assessed by measuring the number of contralateral rotations induced by the dopamine agonist apomorphine. The ability of Sipagladenant to reduce this rotational behavior indicates its anti-parkinsonian potential. |
| ADME/Pharmacokinetics |
Sipagladenant is an orally active, small molecule drug candidate. It has favorable pharmacokinetic properties for CNS indication, including good oral bioavailability and the ability to penetrate the blood-brain barrier. In preclinical species, it demonstrates a dose-proportional increase in plasma exposure. Its half-life supports once-daily dosing. It has a low potential for drug-drug interactions, as it does not appear to be a strong inhibitor or inducer of major CYP450 enzymes.
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| Toxicity/Toxicokinetics |
Sipagladenant has been evaluated in clinical trials for its safety and efficacy. A Phase 1 clinical trial was completed to assess the safety, tolerability, PK, and PD of the compound. In long-term toxicology studies, it was generally well-tolerated. No specific published data on genotoxicity or carcinogenicity is available in the public domain. As an A2A antagonist, adverse events may include nausea, dizziness, or dyskinesia (involuntary movements), which are common to this class of drugs.
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| References |
[1]. https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/pl127.pdf?sfvrsn=8544ca1e_3&download=true
[2]. Horita, Takako. THERAPEUTIC AGENT FOR FRONTAL LOBE DYSFUNCTION, WO2016148308A1. |
| Additional Infomation |
KW-6356 is a selective adenosine A2A receptor antagonist developed by Kyowa Kirin Co., Ltd.
Sipagladenant is a clinical-stage drug candidate developed by Kyowa Kirin for Parkinson's disease and other CNS disorders. As a non-xanthine compound, it is structurally distinct from caffeine and istradefylline, potentially offering a better side effect profile. Its 'insurmountable' antagonism is proposed to provide more sustained receptor blockade compared to surmountable antagonists, which may translate to more consistent clinical efficacy. It is not yet approved for marketing in any major regulatory jurisdiction. |
| Molecular Formula |
C20H19N3O4S
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|---|---|
| Molecular Weight |
397.447563409805
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| Exact Mass |
397.109
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| CAS # |
858979-50-7
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| PubChem CID |
23144148
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
28
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| Complexity |
572
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C(NC(C2C=NC(C)=CC=2)=O)=NC(C2=CC=CO2)=C1C(C1CCOCC1)=O
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| InChi Key |
KMFLQPJJHQNKKF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H19N3O4S/c1-12-4-5-14(11-21-12)19(25)23-20-22-16(15-3-2-8-27-15)18(28-20)17(24)13-6-9-26-10-7-13/h2-5,8,11,13H,6-7,9-10H2,1H3,(H,22,23,25)
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| Chemical Name |
N-[4-(furan-2-yl)-5-(oxane-4-carbonyl)-1,3-thiazol-2-yl]-6-methylpyridine-3-carboxamide
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 : ~50 mg/mL (~125.80 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.29 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5160 mL | 12.5802 mL | 25.1604 mL | |
| 5 mM | 0.5032 mL | 2.5160 mL | 5.0321 mL | |
| 10 mM | 0.2516 mL | 1.2580 mL | 2.5160 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.
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