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An in vitro toolbox to accelerate anti-malarial drug discovery and development.
Malaria Journal ( IF 3 ) Pub Date : 2020-01-02 , DOI: 10.1186/s12936-019-3075-5
Susan A Charman 1 , Alice Andreu 1 , Helena Barker 1 , Scott Blundell 1 , Anna Campbell 1 , Michael Campbell 1 , Gong Chen 1 , Francis C K Chiu 1 , Elly Crighton 1 , Kasiram Katneni 1 , Julia Morizzi 1 , Rahul Patil 1 , Thao Pham 1 , Eileen Ryan 1 , Jessica Saunders 1 , David M Shackleford 1 , Karen L White 1 , Lisa Almond 2 , Maurice Dickins 2 , Dennis A Smith 3 , Joerg J Moehrle 4 , Jeremy N Burrows 4 , Nada Abla 4
Affiliation  

BACKGROUND Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. METHODS Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC-MS/MS. RESULTS Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. CONCLUSIONS This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.

中文翻译:

加速抗疟疾药物发现和开发的体外工具箱。

背景技术越来越多地利用建模和仿真来支持新抗疟药的发现和开发。这些方法需要有关理化性质,通透性,结合,固有清除率和细胞色素P450抑制的可靠体外数据。进行这项工作的目的是使用标准化方法为一组45种抗疟疾药物生成体外数据工具箱,并评估与目标产品和候选药物的变化有关的理化性质的变化。方法通过电位滴定法确定电离常数,并使用摇瓶法测量分配系数。在生物相关介质中评估溶解度,并使用Caco-2细胞单层膜测定渗透系数和外排比。使用超速离心或快速平衡透析测量与血浆和培养基蛋白的结合。使用人肝微粒体评估了代谢稳定性和细胞色素P450抑制作用。样品分析通过LC-MS / MS进行。结果随着Log D7.4的增加,溶解度和未结合分数均降低,通透性和未结合内在清除率均增加。通常,开发化合物比传统药物更具亲脂性。对于许多化合物,通透性和蛋白质结合难以评估,并且都需要使用实验条件,以最大程度地减少非特异性结合的影响。在整个数据集中,人肝微粒体的内在清除率有所不同,几种化合物在所用条件下未显示可测量的底物损失。对于大多数化合物,细胞色素P450酶的抑制作用很小。结论这是描述45种传统抗疟药物和体外抗疟药物体外特性的第一个数据集。研究确定了许多亲脂性化合物共有的几个实用的方法论问题,并着重指出了需要做更多工作来定制化合物的实验条件以适应新目标产品的需要。该数据集将成为疟疾研究人员的宝贵工具,旨在开发用于预测人类PK特性和/或药物相互作用的PBPK模型。此外,
更新日期:2020-01-02
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