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Purity: ≥98%
Istradefylline (formerly KW6002; KW 6002; KW-6002; Nourianz), a caffeine derivative, is an orally bioavailable and selective adenosine A2A receptor (A2AR) antagonist with anti-PD (Parkinson's disease) effects. It suppresses the A2A receptor (A2AR) with a Ki of 2.2 nM. It is authorized for use as a supplement to levodopa/carbidopa in Parkinson's disease patients who are having "off" episodes. Istradefylline lessens the "off" periods brought on by continuous administration of the Parkinson's disease medication levodopa.
| Targets |
Adenosine A2A receptor ( Ki = 2.2 nM )
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| Cell Assay |
The human adenosine A1 or A2A receptor is permanently expressed in a CHO cell line that is cultured in α-MEM supplemented with 10% (v/v) fetal bovine serum, 50 U/mL penicillin, and 50 μg/mL streptomycin. In a 5% CO2 environment, cells are grown at 37°C. These cells are cultivated for twenty-four hours after being seeded at a density of 15,000 cells per well on black 96-well assay plates.
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| Animal Protocol |
The animals are kept in standard housing with a 12-hour light-dark cycle, at a temperature of 24-26°C and a relative humidity of 50–60%. They can be kept in pairs or alone. The diet was composed of fresh fruit, standard food pellets, and marmoset jelly from Mazuri. For five days, the animals receive a daily dosage of 2.0 mg/kg sc of MPTP. The animals are given six to eight weeks to recuperate from the acute effects of MPTP treatment. The animals are hand-fed Mazuri marmoset jelly and fresh fruit puree during MPTP treatment and in the ensuing weeks until they are able to sustain themselves. Prior to behavioral testing, all animals exhibit a significant decrease in basal locomotor activity, slower and less coordinated movements, abnormal postures of some body parts, and a reduction in blinking and checking movements between 6-8 weeks and 8 months after exposure to MPTP. By oral gavage, istradefylline (KW-6002) is given in a final volume of 2.0 mL/kg body weight after being suspended in a solution of 0.3% Tween-80 and 10% sucrose.
Researchers evaluated the efficacy and potency of istradefylline (KW-6002) and other reference compounds in the selective adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680)-, haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on reserpine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)-induced hypolocomotion was also examined. Results: The ED50s of KW-6002 in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively. Compared to the ED50 of other adenosine antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in these models. istradefylline (KW-6002) also ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or reserpine treatment. Combined administrations of subthreshold doses of KW-6002 and L-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there may be a synergism between the adenosine A2A receptor antagonist KW-6002 and dopaminergic agents.[2] |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Istradefylline reaches a Cmax of 181.1ng/mL with a Tmax of 2.0h and an AUC of 11,100ng\*h/mL. M1, the primary active metabolite, reaches a Cmax of 4.34ng/mL with a Tmax of 3.5h. The M8 metabolite reaches a Cmax of 12.6ng/mL with a Tmax of 3.0h and an AUC of 610ng\*h/mL. A 3mg/kg oral dose given to male rats was 17.6% elminated in the urine and 68.3% eliminated in the feces. In urine, 5.31% of the total dose was the M3 metabolite and 1.96% of the total dose was the M1 metabolite. In feces, 30.60% of the total dose was the M3 metabolite, 9.34% of the total dose was the M1 metabolite, 8.33% of the total dose was the M10 metabolite, and 1.62% of the total dose was unchanged istradefylline. The apparent volume of distribution of istradefylline is 448-557L. The apparent clearance of istradefylline is 4.1-6.0L/h. Metabolism / Metabolites The primary metabolite found in urine is the active 4'-O-monodesmethyl istradefylline (M1). Istradefylline is metabolized mainly by CYP1A1, CYP3A4, and CYP3A5. CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP2D6 also partly contribute the the metabolism of istradefylline. Other identified metabolites are 1-β-hydroxylated-4’-O-demethyl istradefylline (M2), 3’,4’-O-didemethyl istradefylline (M3), M1 sulfate conjugate (M4), M1 glucuronide (M5), 1-β-hydroxylated istradefylline (M8) and hydrogenated M3 (M10). Biological Half-Life The terminal elimination half life of istradefylline was 64-69 hours. |
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| Toxicity/Toxicokinetics |
Hepatotoxicity
In prelicensure controlled trials, serum ALT elevations occurred in 4% to 11% of istradefylline-treated subjects compared to 5% to 6% of placebo recipients, most of whom were taking multiple other agents for Parkinson disease. The elevations were usually mild-to-moderate in severity, asymptomatic and self-limited in course. ALT elevations above 3 times the ULN occurred in less than 1% recipients and rarely led to discontinuation. None of the aminotransferase elevations were accompanied by symptoms or jaundice. In preregistration clinical trials and subsequently with its more widespread use, istradefylline has not been linked to instances of clinically apparent liver injury. It has, however, had limited clinical use. Likelihood score: E (unlikely cause of clinically apparent liver injury). Protein Binding Istradefylline is approximately 98% protein bound in plasma, mostly to serum albumin and alpha-1-acid glycoprotein. |
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| Additional Infomation |
Pharmacodynamics
Istradefylline is a selective adenosine A2A receptor inhibitor. It has a long duration of action as it is given once daily and has a half life of 64-69 hours. Patients taking this medication should be monitored for dyskinesia, hallucinations, and lack of impulse control. Consider dose reductions for these patients. |
| Molecular Formula |
C20H24N4O4
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| Molecular Weight |
384.43
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| Exact Mass |
384.179
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| Elemental Analysis |
C, 62.49; H, 6.29; N, 14.57; O, 16.65
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| CAS # |
155270-99-8
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| Related CAS # |
Istradefylline-13C,d3; 2749234-46-4
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| PubChem CID |
5311037
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| Appearance |
Light green to green solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
601.0±65.0 °C at 760 mmHg
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| Melting Point |
189-193
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| Flash Point |
317.3±34.3 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.598
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| LogP |
2.84
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
613
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C2=C(N=C(/C=C/C3=CC(OC)=C(OC)C=C3)N2C)N(CC)C(N1CC)=O
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| InChi Key |
IQVRBWUUXZMOPW-PKNBQFBNSA-N
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| InChi Code |
InChI=1S/C20H24N4O4/c1-6-23-18-17(19(25)24(7-2)20(23)26)22(3)16(21-18)11-9-13-8-10-14(27-4)15(12-13)28-5/h8-12H,6-7H2,1-5H3/b11-9+
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| Chemical Name |
8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methylpurine-2,6-dione
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.41 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 30% Propylene glycol , 5% Tween 80 , 65% D5W: 30mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6013 mL | 13.0063 mL | 26.0125 mL | |
| 5 mM | 0.5203 mL | 2.6013 mL | 5.2025 mL | |
| 10 mM | 0.2601 mL | 1.3006 mL | 2.6013 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05333549 | Recruiting | Drug: Istradefylline | Parkinson Disease Cognitive Impairment |
Virginia Commonwealth University | July 18, 2022 | Phase 2 |
| NCT05182151 | Active Recruiting |
Drug: Istradefylline 40 mg | Parkinson Disease Apathy |
Medical University of South Carolina |
April 6, 2021 | N/A |
| NCT05217498 | Not yet recruiting | Drug: Istradefylline Device: low oxygen therapy |
Spinal Cord Injuries Myelopathy |
Randy Trumbower, PT, PhD | September 1, 2024 | Phase 1 Phase 2 |
| NCT05377424 | Recruiting | Drug: Consume 20mg of istradefylline Other: Low Oxygen therapy |
ALS | University of Florida | June 21, 2022 | Phase 1 Phase 2 |
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