Using Molecular Attributes to Predict Ocular Drug Distribution

描述(由申请人提供)：药物输送到特定的眼组织是一个主要的挑战，因为药物摄取和眼内分布所需的因素在很大程度上仍未确定。分子描述符越来越多地被用来定义和模拟药物的药理I药代动力学特性。这项建议引入了一种新的眼部药物输送和分配方法，通过建立药物上的特定分子描述符可以用来将分子“引导”到其特定的眼部靶组织。这 是基于我们的发现，即选定的分子属性I描述符似乎指导我们实验室合成的口服多功能抗氧化剂(MFAO)的摄取和分布到晶状体、神经视网膜和大脑。这项建议寻求通过6个MFOA扩展这一初步观察，将研究扩大到24个化合物，包括母体和单功能类似物。分子属性/描述符将使用分子操作环境(MOE)软件以及专门为优化电子药物动力学特性而设计的Volsurf软件获得。这将与在角膜、虹膜/睫状体、晶状体、神经视网膜和成年大鼠眼后段剩余部分(RPE、脉络膜、巩膜)以及脑、肝、肾和周围(坐骨神经)中获得的药物水平相关。在体内定量结构活性关系(QSAR)模型中建立的相关性将通过随后对从该模型设计的测试化合物的评估来验证，然后在大鼠身上合成和评估。经过验证的模型不仅允许我们预测MFAO的组织摄取，而且还将建立一个基于其他药物的分子属性/描述符来预测组织摄取的模型。

DESCRIPTION (provided by applicant): Drug delivery to specific ocular tissues is a major challenge because the factors required for the uptake and ocular distribution of drugs remains largely undefined. Molecular descriptors are increasingly being used to define and model the pharmacological I pharmacokinetic properties of drugs. This proposal introduces a new approach to ocular drug delivery and distribution by establishing that specific molecular descriptors on a drug can be used to "guide" a molecule to its specific ocular target tissue. This is based on our finding that select molecular attributes I descriptors appear to guide the uptake and distribution of orally administered multifunctional antioxidants (MFAOs) synthesized in our laboratory into the lens, neural retina, and brain. This proposal seeks to expand on this initial observation with 6 MFOAs by expanding the study to 24 compounds that include the parent and mono- functional analogs. Molecular attributes/descriptors will be obtained using Molecular Operating Environment (MOE) software as well as Volsurf software that is especially designed for optimizing in silico pharmacokinetic properties. These will be correlated with drug levels obtained in the cornea, iris/ciliary body, lens, neural retina and the remaining posterior segment (RPE, choroid, sclera) of adult rat eyes as well as brain, liver, kidney, and peripheral (sciatic) nerve. The correlations established in the in vivo quantitative structure activity relationship (QSAR) model will be validated by the subsequent evaluation of test compounds that are designed from the model and then synthesized and evaluated in rats. The validated model will not only allow us to predict the tissue uptake of MFAOs, but will also establish a model for predicting the tissue uptake of other drugs based on their molecular attributes / descriptors.