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更新于：2025-03-24
AZD-1305
更新于：2025-03-24
概要
基本信息
药物类型 小分子化药 |
别名 AZD 1305、AZD1305 |
作用方式 阻滞剂 |
作用机制 L-type calcium channel阻滞剂(L-型电压门控性钙通道家族阻滞剂)、Nav1.5阻滞剂(V型钠通道蛋白α亚基阻滞剂)、hERG阻滞剂(电压门控性钾通道蛋白亚型Kv11.1阻滞剂) |
治疗领域 |
在研适应症- |
原研机构 |
在研机构- |
最高研发阶段终止临床2期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
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结构/序列
分子式C22H31FN4O4 |
InChIKeyBLLNYXOLLAVTRF-UHFFFAOYSA-N |
CAS号872045-91-5 |
关联
14
项与 AZD-1305 相关的临床试验NCT00957437
A Phase I, Randomised, Open, Single-centre Study to Evaluate the Pharmacokinetics of Different Extended-release Formulations of AZD1305 When Given as Single and Repeated Oral Doses to Healthy Male Volunteers
NCT00935025
A Single-center, Single-blind, Randomized, Placebo-controlled, Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics After Single and Multiple Ascending Oral Doses of AZD1305 Extended-release Capsules in Healthy Male Japanese and Caucasian Subjects
EUCTR2009-009862-15-CZ
A double-Blind, Randomised, Placebo-Controlled, Multicentre, Dose-Escalating Study of AZD1305 Given Intravenoulsy for Cardioversion of Atrial Fibrillation
100 项与 AZD-1305 相关的临床结果
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100 项与 AZD-1305 相关的转化医学
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100 项与 AZD-1305 相关的专利（医药）
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19
项与 AZD-1305 相关的文献（医药）2024-07-01EBioMedicine
Advancing drug development for atrial fibrillation by prioritising findings from human genetic association studies
Article
作者: Providencia, Rui ; Lambiase, Pier D ; Finan, Chris ; Schilling, Richard ; Floriaan Schmidt, Amand ; Kukendrarajah, Kishore ; Farmaki, Aliki-Eleni
BACKGROUND:
Drug development for atrial fibrillation (AF) has failed to yield new approved compounds. We sought to identify and prioritise potential druggable targets with support from human genetics, by integrating the available evidence with bioinformatics sources relevant for AF drug development.
METHODS:
Genetic hits for AF and related traits were identified through structured search of MEDLINE. Genes derived from each paper were cross-referenced with the OpenTargets platform for drug interactions. Confirmation/validation was demonstrated through structured searches and review of evidence on MEDLINE and ClinialTrials.gov for each drug and its association with AF.
FINDINGS:
613 unique drugs were identified, with 21 already included in AF Guidelines. Cardiovascular drugs from classes not currently used for AF (e.g. ranolazine and carperitide) and anti-inflammatory drugs (e.g. dexamethasone and mehylprednisolone) had evidence of potential benefit. Further targets were considered druggable but remain open for drug development.
INTERPRETATION:
Our systematic approach, combining evidence from different bioinformatics platforms, identified drug repurposing opportunities and druggable targets for AF.
FUNDING:
KK is supported by Barts Charity grant G-002089 and is mentored on the AFGen 2023-24 Fellowship funded by the AFGen NIH/NHLBI grant R01HL092577. RP is supported by the UCL BHF Research Accelerator AA/18/6/34223 and NIHR grant NIHR129463. AFS is supported by the BHF grants PG/18/5033837, PG/22/10989 and UCL BHF Accelerator AA/18/6/34223 as well as the UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee EP/Z000211/1 and by the UKRI-NIHR grant MR/V033867/1 for the Multimorbidity Mechanism and Therapeutics Research Collaboration. AF is supported by UCL BHF Accelerator AA/18/6/34223. CF is supported by UCL BHF Accelerator AA/18/6/34223.
2018-06-01British Journal of Pharmacology
Human hepatocytes and cytochrome P450‐selective inhibitors predict variability in human drug exposure more accurately than human recombinant P450s
Article
作者: Lundahl, Anna ; Lindmark, Bo ; Andersson, Tommy B ; Isin, Emre M ; Kanebratt, Kajsa P
Background and Purpose:
Drugs metabolically eliminated by several enzymes are less vulnerable to variable compound exposure in patients due to drug–drug interactions (DDI) or if a polymorphic enzyme is involved in their elimination. Therefore, it is vital in drug discovery to accurately and efficiently estimate and optimize the metabolic elimination profile.
Experimental Approach:
CYP3A and/or CYP2D6 substrates with well described variability in vivo in humans due to CYP3A DDI and CYP2D6 polymorphism were selected for assessment of fraction metabolized by each enzyme (fmCYP) in two in vitro systems: (i) human recombinant P450s (hrP450s) and (ii) human hepatocytes combined with selective P450 inhibitors. Increases in compound exposure in poor versus extensive CYP2D6 metabolizers and by the strong CYP3A inhibitor ketoconazole were mathematically modelled and predicted changes in exposure were compared with in vivo data.
Key Results:
Predicted changes in exposure were within twofold of reported in vivo values using fmCYP estimated in human hepatocytes and there was a strong linear correlation between predicted and observed changes in exposure (r2 = 0.83 for CYP3A, r2 = 0.82 for CYP2D6). Predictions using fmCYP in hrP450s were not as accurate (r2 = 0.55 for CYP3A, r2 = 0.20 for CYP2D6).
Conclusions and Implications:
The results suggest that variability in human drug exposure due to DDI and enzyme polymorphism can be accurately predicted using fmCYP from human hepatocytes and CYP‐selective inhibitors. This approach can be efficiently applied in drug discovery to aid optimization of candidate drugs with a favourable metabolic elimination profile and limited variability in patients.
2017-10-01British Journal of Pharmacology
Predicting QRS and PR interval prolongations in humans using nonclinical data
Article
作者: Collins, T ; Mettetal, J ; Parkinson, J ; Chappell, M J ; Bergenholm, L ; Evans, N D
Background and Purpose:
Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase.
Experimental Approach:
Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration‐matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model.
Key Results:
Meaningful (10%) human QRS/PR effects correlated with low levels of in vitro Nav1.5 block (3–7%) and Cav1.2 binding (13–21%) for all compounds. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. Meaningful QRS/PR changes in humans correlated with small effects in guinea pigs and dogs (QRS 2.3–4.6% and PR 2.3–10%), suggesting that worst‐case human effects can be predicted by assuming four times greater effects at the same concentration from dog/guinea pig data.
Conclusion and Implications:
Small changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non–arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies.
100 项与 AZD-1305 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 左心室功能不全 | 临床2期 | 瑞典 | 2008-08-01 | |
| 心房颤动 | 临床2期 | 丹麦 | 2008-03-01 | |
| 心房颤动 | 临床2期 | 挪威 | 2008-03-01 | |
| 心房颤动 | 临床2期 | 波兰 | 2008-03-01 | |
| 心房颤动 | 临床2期 | 俄罗斯 | 2008-03-01 | |
| 心房颤动 | 临床2期 | 斯洛伐克 | 2008-03-01 | |
| 心房颤动 | 临床2期 | 瑞典 | 2008-03-01 | |
| 心房扑动 | 临床2期 | 丹麦 | 2008-01-01 | |
| 心房扑动 | 临床2期 | 芬兰 | 2008-01-01 | |
| 心房扑动 | 临床2期 | 挪威 | 2008-01-01 |
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临床结果
临床结果
适应症
分期
评价
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临床2期 | 228 | (AZD1305 Dose Group 1) | 簾衊製壓壓衊築艱窪鹹(積蓋鹹積餘衊廠廠鏇餘) = 獵蓋夢簾鑰鹹醖齋壓鏇 窪膚遞鬱淵範壓築襯憲 (鏇遞鹽網製蓋憲鏇遞齋, 艱網醖夢鑰衊構餘構壓 ~ 築鏇廠繭衊製鹽積鹽網) 更多 | - | 2012-02-01 | ||
(AZD1305 Dose Group 2) | 簾衊製壓壓衊築艱窪鹹(積蓋鹹積餘衊廠廠鏇餘) = 繭鬱築遞窪選壓簾齋鹹 窪膚遞鬱淵範壓築襯憲 (鏇遞鹽網製蓋憲鏇遞齋, 範鹹願積夢網網餘衊艱 ~ 選觸壓積網鑰餘顧餘簾) 更多 | ||||||
临床2期 | 65 | (AZD1305 Group A and AZD1305 Group B) | 願築網築鏇顧鑰夢範鹹(鹽糧選淵鹹範憲衊製蓋) = 顧鹽構鑰艱觸築積鹽繭 餘餘簾鑰膚獵襯餘選願 (觸鏇鏇觸鹹蓋構衊顧衊, 構憲簾選選選觸願構齋 ~ 窪網窪壓網鏇襯壓簾夢) 更多 | - | 2012-01-26 | ||
Placebo+AZD1305 (Placebo) | 願築網築鏇顧鑰夢範鹹(鹽糧選淵鹹範憲衊製蓋) = 鑰鹹範窪繭淵壓憲簾餘 餘餘簾鑰膚獵襯餘選願 (觸鏇鏇觸鹹蓋構衊顧衊, 獵鏇淵廠淵願積觸範餘 ~ 簾衊築壓範鏇鹹壓鹽艱) 更多 | ||||||
临床2期 | 171 | 廠鏇繭遞憲鹽衊觸選膚(鑰簾窪選獵窪壓鹽淵淵) = 築艱夢餘膚襯艱願範憲 蓋齋鏇築窪窪膚窪顧廠 (夢製製範製鏇餘顧選鬱 ) 更多 | 不佳 | 2011-08-01 | |||
临床2期 | 16 | (AZD1305 Dose 1 and Dose 2) | 衊夢繭顧夢鹽願壓簾艱(鹽襯壓繭網艱簾憲膚鏇) = 顧鏇膚窪鹹鏇襯製艱鑰 餘鏇艱醖鹽鏇襯顧鹹廠 (簾醖鏇製範鏇廠選顧夢, 齋範鑰觸壓鏇鹹餘鏇繭 ~ 餘積鏇鹽積醖鬱廠醖蓋) 更多 | - | 2011-06-13 | ||
Placebo (Placebo Dose 1 and Dose 2) | 衊夢繭顧夢鹽願壓簾艱(鹽襯壓繭網艱簾憲膚鏇) = 顧廠範鑰築衊鹹繭衊壓 餘鏇艱醖鹽鏇襯顧鹹廠 (簾醖鏇製範鏇廠選顧夢, 齋齋醖壓夢壓鹽衊糧獵 ~ 壓繭鬱襯築積顧範膚憲) 更多 |
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