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AZD8154 Sale

目录号 : GC65507

AZD8154 是一种新型吸入的选择性 PI3Kγδ 双抑制剂,靶向气道炎症性疾病。

AZD8154 Chemical Structure

Cas No.:2215022-45-8

规格 价格 库存 购买数量
5mg
¥5,850.00
现货
10mg
¥8,820.00
现货

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Sample solution is provided at 25 µL, 10mM.

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产品描述

AZD8154 is a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease.

[1]. Sadiq MW, et al. Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease. Br J Clin Pharmacol. 2021 Jun 28.

Chemical Properties

Cas No. 2215022-45-8 SDF Download SDF
分子式 C27H29N5O4S2 分子量 551.68
溶解度 DMSO : 25 mg/mL (45.32 mM; Need ultrasonic) 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 1.8126 mL 9.0632 mL 18.1265 mL
5 mM 0.3625 mL 1.8126 mL 3.6253 mL
10 mM 0.1813 mL 0.9063 mL 1.8126 mL
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Research Update

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma

J Med Chem 2021 Jun 24;64(12):8053-8075.PMID:34080862DOI:10.1021/acs.jmedchem.1c00434.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease

Br J Clin Pharmacol 2022 Jan;88(1):260-270.PMID:34182611DOI:10.1111/bcp.14956.

Aims: This 3-part, randomised, phase 1 first-in-human study (NCT03436316) investigated the safety, tolerability and pharmacokinetics (PK) of AZD8154, a dual phosphoinositide 3-kinase (PI3K) γδ inhibitor developed as a novel inhaled anti-inflammatory treatment for respiratory disease. Methods: Healthy men, and women of nonchildbearing potential, were enrolled to receive single and multiple ascending inhaled doses of AZD8154 in parts 1 and 3 of the study, respectively, while part 2 characterised the systemic PK after a single intravenous (IV) dose. In part 1, participants received 0.1-7.7 mg AZD8154 in 6 cohorts. In part 2, participants were given 0.15 mg AZD8154 as an IV infusion. In part 3, AZD8154 was given in 3 cohorts of 0.6, 1.8 and 3.1 mg, with a single dose on Day 1 followed by repeated once-daily doses on Days 4-12. Results: In total, 78 volunteers were randomised. All single inhaled, single IV and multiple inhaled doses were shown to be well tolerated without any safety concerns. A population PK model, using nonlinear mixed-effect modelling, was developed to describe the PK of AZD8154. The terminal mean half-life of AZD8154 was 18.0-32.0 hours. The geometric mean of the absolute pulmonary bioavailability of AZD8154 via the inhaled route was 94.1%. Conclusion: AZD8154 demonstrated an acceptable safety profile, with no reports of serious adverse events and no clinically significant drug-associated safety concerns reported in healthy volunteers. AZD8154 demonstrated prolonged lung retention and a half-life supporting once-daily dosing.

Diurnal variation in DLCO and non-standardized study procedures may cause a false positive safety signal in clinical trials

Respir Med 2022 Jan;191:106705.PMID:34879298DOI:10.1016/j.rmed.2021.106705.

Diffusing capacity for carbon monoxide (DLCO) was measured in a phase I single ascending dose study after inhalation of AZD8154 or placebo in healthy participants at baseline (DLCOBaseline) and follow-up (DLCOFollow-up) 6 days after dosing. Initially, DLCOFollow-up timepoint was 2 h earlier than the DLCOBaseline timepoint and clinically significant decreases in DLCOFollow-up (absolute change up to 19% from baseline and DLCO%predicted values less than 70) were observed then. The observed reduction in DLCOFollow-up was confirmed as a false positive finding after alignment of DLCO timings. As a consequence, when DLCO is used in clinical studies, measurements should be strictly standardized in relation to time of the day.