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Purity: ≥98%
AZD1283 is a novel, potent and selective antagonist of the P2Y12 receptor with EC50 of 3.0 ug/kg/min, TI >10 and with binding IC50 of 11 nM. AZD1283 demonstrated dose-dependent increases in blood flow and inhibition of ADP-induced platelet aggregation in a modified Folts model in dogs, with antithrombotic ED50 values of 3.0 μg/kg/min. The doses of 33 μg/kg/min caused a bleeding time increase greater than threefold. As a result, TI (therapeutic index) was less than 10. Based on these findings, AZD1283 was advanced into human clinical trials as a potential medication.
| Targets |
P2Y12 Receptor ( IC50 = 11 nM )
AZD1283 has an IC50 value of 3.6 μM, demonstrating good antiplatelet aggregation potency[1]. AZD1283 exhibits strong inhibitory effects on CYP450, as evidenced by its IC50 values of 6.62 μM, 0.399 μM, 4.28 μM, and 3.64 μM for CYP2C9, CYP2C19, CYP3A4 (requiring midazolam as substrate), and CYP3A4 (requiring testosterone as substrate), respectively[1]. AZD1283 has an antithrombotic EC50 value of 3 μg/(kg×min) and increases blood flow while inhibiting ADP-induced platelet aggregation[2]. |
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| ln Vitro |
AZD1283 has an IC50 value of 3.6 μM, demonstrating good antiplatelet aggregation potency[1].
AZD1283 exhibits strong inhibitory effects on CYP450, as evidenced by its IC50 values of 6.62 μM, 0.399 μM, 4.28 μM, and 3.64 μM for CYP2C9, CYP2C19, CYP3A4 (requiring midazolam as substrate), and CYP3A4 (requiring testosterone as substrate), respectively[1]. AZD1283 has an antithrombotic EC50 value of 3 μg/(kg×min) and increases blood flow while inhibiting ADP-induced platelet aggregation[2]. AZD1283 exhibited an IC50 of 3.60 µM in an ADP-induced (10 µM) human platelet-rich plasma (PRP) aggregation assay. [1] AZD1283 showed strong inhibition of CYP2C19 (IC50 = 0.399 µM) and moderate inhibition of CYP2C9 (IC50 = 6.62 µM) and CYP3A4 (IC50 = 4.28 µM for midazolam, 3.64 µM for testosterone) in a CYP450 inhibition assay. [1] |
| ln Vivo |
AZD1283 shows inadequate liver microsomal stability in rats (T1/2 = 6.08 min), but better in dog and human microsomes (T1/2 = 201 and 65.0 min)[1].
In a rat ferric chloride (FeCl3)-induced arterial thrombosis model, oral administration of AZD1283 at 10 mg/kg caused no significant difference in thrombus weight compared to the vehicle control group. [1] |
| Enzyme Assay |
For the in vitro platelet aggregation assay, human platelet-rich plasma (PRP) was prepared by centrifuging blood at 300 g for 10 min. Platelet-poor plasma (PPP) was obtained by further centrifugation at 2000 g for 10 min. Aggregation was analyzed using a double-channel aggregometer at 37°C with stirring. PRP was incubated with test compounds (final concentrations: 3, 10, 30, 100, 300 µM in 0.5% DMSO) or vehicle for 2 min at 37°C. Platelets were then stimulated with ADP (10 µM final concentration). Aggregation was monitored for 5 min by recording optical density variations. The inhibition rate was calculated, and IC50 values were determined by nonlinear regression. [1]
For the CYP450 inhibition cocktail assay, experiments were performed in 96-well plates. Human liver microsomes, test compound or positive control inhibitor, and specific probe substrates for each CYP450 isoform (phenacetin for CYP1A2, tolbutamide for CYP2C9, mephenytoin for CYP2C19, dextromethorphan for CYP2D6, midazolam and testosterone for CYP3A4) were incubated in Tris buffer (pH 7.4). After pre-incubation at 37°C for 10 min, the reaction was initiated by adding NADPH (1 mM final concentration). The plates were incubated at 37°C for 15 min before quenching with acetonitrile containing internal standards. After centrifugation, supernatants were analyzed by LC/MS/MS. The inhibition rate was determined at five different compound concentrations, and IC50 values were calculated. [1] |
| Animal Protocol |
Sprague-Dawley rats
5 mg/kg p.o.; single dosage For the rat FeCl3 thrombosis model, male Wistar rats (250-300 g) were used. AZD1283 or vehicle was suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered orally at 10 mg/kg (10 mL/kg). At 1.5 hours post-dosing, rats were anesthetized. A segment of the left carotid artery was isolated. A filter paper saturated with 20% FeCl3 was placed on the artery for 10 min to induce thrombus formation. Thirty minutes later, the artery was dissected, the thrombus was removed, cleaned, dried, and weighed. [1] For rat pharmacokinetic studies, male Sprague-Dawley rats (200-220 g) were used. AZD1283 (formulated in 5% DMSO + 95% HPMC) was administered orally at 5 mg/kg. Blood samples were collected via the retrobulbar vein at specified time points up to 24 hours. Plasma concentrations were quantified by LC/MS/MS. [1] |
| ADME/Pharmacokinetics |
In rat liver microsomes, AZD1283 exhibits extremely poor metabolic stability, with an elimination half-life (T1/2) of 6.08 min, an intrinsic clearance (Clint) of 345 mL/min/g protein, and a metabolic bioavailability (MF%) of 11.0%. In canine liver microsomes, the T1/2 is 201 min, the Clint is 11.2 mL/min/g protein, and the MF% is 66.0%. In human liver microsomes, the T1/2 is 65.0 min, the Clint is 32.3 mL/min/g protein, and the MF% is 38.0%. [1]
After a single oral dose of 5 mg/kg in male Sprague-Dawley rats, AZD1283 showed poor pharmacokinetic characteristics: peak plasma concentration (Cmax) was 25.9 ± 11 ng/mL, time to peak concentration (Tmax) was 0.25 h, elimination half-life (T1/2) was 1.68 ± 0.37 h, area under the concentration-time curve (AUC0-∞) was 34.0 ± 3.34 ng·h/mL, and mean residence time (MRT) was 2.67 ± 0.77 h. [1] The solubility of AZD1283 was determined in different matrices: the maximum solubility was 15.61 ± 6.40 µM in intestinal fluid, 0.51 ± 0.20 µM in gastric fluid (pH 1.2), and 2.99 ± 1.80 µM in water. [1] |
| Toxicity/Toxicokinetics |
However, it is noteworthy that AZD1283 inhibits multiple CYP450 enzymes (CYP2C9, CYP3A4, and CYP2C19), suggesting a possible drug interaction. [1] In human ether activation-associated gene (hERG) assays, the novel optimized compound 58l (derived from AZD1283) did not show inhibitory activity at concentrations up to 40 µM, but this data is not specific to AZD1283 itself. [1]
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| References |
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| Additional Infomation |
AZD1283 is an orally administered reversible P2Y12 receptor antagonist reported by AstraZeneca. It showed strong antithrombotic efficacy and reduced bleeding risk in animal models and entered human clinical trials. However, its development was terminated before Phase II clinical trials due to poor absorption and low ester metabolic stability. [1] The X-ray crystal structure of AZD1283 bound to the human P2Y12 receptor showed that the hydrogen bond between the ester carbonyl group and Asn159 was crucial for its high affinity. This finding guided the design of more stable analogs by cyclizing the ester group. [1]
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| Molecular Formula |
C23H26N4O5S
|
|---|---|
| Molecular Weight |
470.541344165802
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| Exact Mass |
470.162
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| Elemental Analysis |
C, 58.71; H, 5.57; N, 11.91; O, 17.00; S, 6.81
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| CAS # |
919351-41-0
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| PubChem CID |
23649325
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.618
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| LogP |
2.66
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
33
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| Complexity |
835
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N#CC1C(N2CCC(C(NS(CC3C=CC=CC=3)(=O)=O)=O)CC2)=NC(C)=C(C(OCC)=O)C=1
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| InChi Key |
NEMHKCNXXRQYRF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H26N4O5S/c1-3-32-23(29)20-13-19(14-24)21(25-16(20)2)27-11-9-18(10-12-27)22(28)26-33(30,31)15-17-7-5-4-6-8-17/h4-8,13,18H,3,9-12,15H2,1-2H3,(H,26,28)
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| Chemical Name |
ethyl 6-[4-(benzylsulfonylcarbamoyl)piperidin-1-yl]-5-cyano-2-methylpyridine-3-carboxylate
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| Synonyms |
AZD-1283; AZD1283; AZD 1283
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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 (~212.5 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.31 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 25.0 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: ≥ 2.5 mg/mL (5.31 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 25.0 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 | 2.1252 mL | 10.6261 mL | 21.2522 mL | |
| 5 mM | 0.4250 mL | 2.1252 mL | 4.2504 mL | |
| 10 mM | 0.2125 mL | 1.0626 mL | 2.1252 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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