AZD7325
(Synonyms: BAER-101) 目录号 : GC39342
A positive allosteric modulator of α2- and α3 subunit-containing GABAA receptors
Cas No.:942437-37-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
AZD 7325 is a positive allosteric modulator of α2- and α3 subunit-containing GABAA receptors and a neutral antagonist for α1 subunit-containing GABAA receptors.1 It binds to GABAA receptors in membranes from Sf9 cells expressing α2β3γ2 subunit-containing receptors (Ki = 0.309 nM). AZD 7325 (1 mg/kg) increases marble-burying behavior, indicating anxiety-like activity, and decreases audiogenic seizure severity in the Fmr1-/- mouse model of fragile X syndrome.2
1.Alhambra, C., Becker, C., Blake, T.A., et al.Development and SAR of functionally selective allosteric modulators of GABAA receptorsBioorg. Med. Chem.19(9)2927-2938(2011) 2.Schaefer, T.L., Ashworth, A.A., Tiwari, D., et al.GABAA alpha 2,3 modulation improves select phenotypes in a mouse model of fragile X syndromeFront. Psychiatry12678090(2021)
| Cas No. | 942437-37-8 | SDF | |
| 别名 | BAER-101 | ||
| Canonical SMILES | O=C(C1=NN=C2C(C3=C(OC)C=CC=C3F)=CC=CC2=C1N)NCCC | ||
| 分子式 | C19H19FN4O2 | 分子量 | 354.38 |
| 溶解度 | DMSO: 250 mg/mL (705.46 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.8218 mL | 14.1091 mL | 28.2183 mL |
| 5 mM | 0.5644 mL | 2.8218 mL | 5.6437 mL |
| 10 mM | 0.2822 mL | 1.4109 mL | 2.8218 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
The impact of radiochemistry in drug projects: The use of C-14 label in the AZD8529, AZD7325, and AZD6280 projects
J Labelled Comp Radiopharm 2021 Feb;64(2):65-72.PMID:33326121DOI:10.1002/jlcr.3902.
Understanding the metabolic transformations of a potential drug molecule is important to understanding the safety profile of a drug candidate. Liquid chromatography-mass spectrometry is a standard method for detecting metabolites in the drug discovery stage, but this can lead to an incomplete understanding of the molecule's metabolism. In this manuscript, we highlight the role radiolabeling played in determining the metabolism and in quantifying the metabolites of AZD8529, AZD7325, and AZD6280. A quantitative whole-body autoradiography study can detect covalent adducts in vivo as was the case with AZD5248 in which the compound was bound to the aorta. Ultimately another compound free of aortic binding was developed, AZD7986.
Population pharmacokinetic modelling to assess clinical drug-drug interaction between AZD7325 and midazolam
J Clin Pharm Ther 2014 Aug;39(4):404-10.PMID:24689515DOI:10.1111/jcpt.12152.
What is known and objective: AZD7325 is a selective gamma-amino-butyric acid (GABAA )α2, 3 receptor modulator. The aims of this analysis were to develop population pharmacokinetic (PPK) models of AZD7325 and midazolam and to assess the induction effect of AZD7325 on CYP3A4 with midazolam as a substrate. Methods: Drug-drug interaction data of AZD7325 and midazolam from 24 healthy subjects were available for model development. PPK models were developed in a sequential manner using NONMEM. Both AZD7325 and midazolam pharmacokinetics were described by two-compartment models, and a transit compartment absorption model and a first-order absorption model were applied for the absorption of AZD7325 and midazolam, respectively. The induction of CYP3A by AZD7325 was described by a transit enzyme model, where the elimination of midazolam was proportionally linked to the enzyme amount. Simulations were performed to predict dosing regimens to account for the induction of CYP3A4. Results and discussion: The population estimates for AZD7325 clearance, intercompartmental clearance, central and peripheral volume were 36, 29·2 L/h, 169 and 392 L, respectively, with interindividual variability (IIV) of 35% and 24% for clearance and central volume. Midazolam clearance, intercompartmental clearance, central and peripheral volume were estimated to be 62·7, 34·7 L/h, 133 and 146 L, respectively, with 43% IIV for clearance. The estimated mean transit time for induction of the CYP3A4 enzyme was 197 h, with 57% IIV. What is new and conclusion: The PPK models developed adequately described the clinical observation of AZD7325-mediated CYP3A4 enzyme induction with midazolam as a probe. The model could provide basis for the rational dosing of AZD7325 in clinical practice.
A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABA(A) receptor modulator - an in vitro and in vivo comparison
Br J Clin Pharmacol 2012 Jul;74(1):98-108.PMID:22122233DOI:10.1111/j.1365-2125.2011.04155.x.
What is already known about this subject: • AZD7325 is an orally administered, potent, selective gamma-amino-butyric acid (GABA(A) ) α2,3 receptor modulator intended for the treatment of anxiety. • The induction effects of AZD7325 on CYP1A2 and CYP3A4 have not been systematically studied. What this study adds: • The in vitro studies showed that AZD7325 was a moderate CYP1A2 inducer and potent CYP3A4 inducer. • The follow-up clinical studies in healthy volunteers demonstrated that the expected efficacious daily dose of AZD7325 only weakly induced the pharmacokinetics of the CYP3A4 sensitive substrate, midazolam, and had no effect on the pharmacokinetics of the CYP1A2 substrate, caffeine. There was no apparent change in AZD7325 exposure following co-administration of midazolam or caffeine compared with AZD7325 alone. • The study demonstrated that clinical exposure of the inducer plays a critical role in the determination of cytochrome P450 induction risk of a drug candidate. Aim(s): To investigate the potential of AZD7325 to induce CYP1A2 and CYP3A4 enzyme activities. Methods: Induction of CYP1A2 and CYP3A4 by AZD7325 was first evaluated using cultured human hepatocytes. The effect of multiple doses of 10 mg AZD7325 on the pharmacokinetics of midazolam and caffeine was then examined in healthy subjects. Results: The highest CYP1A2 and CYP3A4 induction responses were observed in human hepatocytes treated with 1 or 10 µm of AZD7325, in the range of 17.9%-54.9% and 76.9%-85.7% of the positive control responses, respectively. The results triggered the further clinical evaluation of AZD7325 induction potential. AZD7325 reached a plasma C(max) of 0.2 µm after 10 mg daily dosing to steady-state. AZD7325 decreased midazolam geometric mean AUC by 19% (0.81-fold, 90% CI 0.77, 0.87), but had no effect on midazolam C(max) (90% CI 0.82, 0.97). The mean CL/F of midazolam increased from 62 l h(-1) (midazolam alone) to 76 l h(-1) when co-administered with AZD7325. The AUC and C(max) of caffeine were not changed after co-administration of AZD7325, with geometric mean ratios (90% CI) of 1.17 (1.12, 1.23) and 0.99 (0.95, 1.03), respectively. Conclusions: While AZD7325 appeared to be a potent CYP3A4 inducer and a moderate CYP1A2 inducer from in vitro studies, the expected efficacious dose of AZD7325 had no effect on CYP1A2 activity and only a weak inducing effect on CYP3A4 activity. This comparison of in vitro and in vivo results demonstrates the critical role that clinical exposure plays in evaluating the CYP induction risk of a drug candidate.
Synthesis of C-14 labeled GABAA α2/α3 selective partial agonists and the investigation of late-occurring and long-circulating metabolites of GABAA receptor modulator AZD7325
J Labelled Comp Radiopharm 2018 May 15;61(5):415-426.PMID:29314165DOI:10.1002/jlcr.3602.
Anxiolytic activity has been associated with GABAA α2 and α3 subunits. Several target compounds were identified and required in C-14 labeled form to enable a better understanding of their drug metabolism and pharmacokinetic properties. AZD7325 is a selective GABAA α2 and α3 receptor modulator intended for the treatment of anxiety through oral administration. A great number of AZD7325 metabolites were observed across species in vivo, whose identification was aided by [14 C]AZD7325. An interesting metabolic cyclization and aromatization pathway leading to the tricyclic core of M9 and the oxidative pathways to M10 and M42 are presented.
The central nervous system effects of the partial GABA-Aα2,3 -selective receptor modulator AZD7325 in comparison with lorazepam in healthy males
Br J Clin Pharmacol 2014 Dec;78(6):1298-314.PMID:24802722DOI:10.1111/bcp.12413.
Aims: AZD7325 is a novel α2,3 -subtype-selective partial GABA-A-receptor modulator. This study investigated the pharmacodynamics of single oral doses of AZD7325 2 mg and 10 mg on the central nervous system (CNS) compared with placebo and lorazepam 2 mg. Methods: This double-blind, randomized, four way crossover study enrolled 16 healthy males and administered two validated CNS test batteries to measure drug effects on cognitive, neurophysiologic and psychomotor function and subjective feelings. The pharmacological selectivity of AZD7325 was compared with lorazepam by plotting saccadic peak velocity change from baseline (ΔSPV) against body sway (ΔSway) and visual analogue scale for alertness(ΔVASalertness ). This analysis has previously been used to identify α2,3 -subtype-selectivity. Results: In contrast with the robust impairment caused by lorazepam (all P < 0.05 vs. placebo), neither dose of AZD7325 induced statistically significant effects on any pharmacodynamic measurements. Lorazepam-induced SPV-reduction was linearly related to changes in other neurophysiologic biomarkers. In contrast, the slopes of the regression lines were flatter for AZD7325, particularly for the Δlog(Sway) -ΔSPV relation (estimate slope, AZD7325 10 mg vs. lorazepam, difference [95% confidence interval], P value -0.00036 vs. -0.00206, 0.001704 [0.000639, 0.002768], P = 0.0018) and the ΔVASalertness -ΔSPV relationship (0.01855 vs. 0.08216, -0.06360 [-0.1046, -0.02257], P = 0.0024). AZD7325 10 mg and lorazepam induced different response patterns on VAS 'feeling high' and electro-encephalography. Conclusion: The characteristic ΔSPV-relative effect profiles of AZD7325 vs. lorazepam suggest anxio-selectivity related to α2,3 -selective GABAA agonism. However, exploration of higher doses may be warranted. The paucity of effects on most CNS-PD parameters also indicates a mitigated side effect pattern, with potentially lower cognitive and neurophysiological side effect burden than non-selective benzodiazepines.