SURFACE-ACTIVE ANTITHROMBOTIC AGENTS FOR PROSTHESES

该项目旨在开发新型合成化合物， 稳定血小板膜。 其中一个主要目标是 帮助特别易患血栓栓塞并发症的个体 因为他们的血液接触了生物材料， 假肢装置和体外设备。 在这篇文章中，小说 分子实体将使用三管齐下的方法获得：（i） 由于对映体选择性在药物作用中的重要性， 他们之前研究中最活跃的三种化合物是 拆分成3种立体异构体。 单独的对映异构体和 将测试非对映异构体对人血的抑制作用 体外血小板聚集，由人α-凝血酶，胶原， 和肾上腺素 (ii)这3种化合物的外消旋类似物将是 合成，以延长其作用时间，和（iii） 在结构上，电子密度和电子密度将得到优化。 以前没有检查过的组件。 显示合理效力的化合物 在初步筛选中，将评价其体外作用，（a） 对胞浆离子钙（[Ca. 2+]）浓度，（B） 血小板因子4（PF-4）、血小板因子3（PF-3）和5-羟色胺，和（c） 在小鼠体内的急性毒性。 与莱斯大学的拉里·V·麦金太尔博士合作， 将研究选定化合物的人体血液动力学 血小板粘附和血栓生长受胶原和 平行板流动室系统中的生物材料。 将测试一种或两种高活性和毒性最小的化合物， 血小板聚集抑制活性，离体，在狗中。 的 将在小鼠和狗中评价相同化合物的药代动力学， 和生物利用度。 尿液中发现的代谢物的结构将 使用HPLC-MS建立。 由于许多生物系统的手性环境， 预期这些合成化合物的对映选择性 发现增加的抗血栓效力，同时， 毒性较小。 结构特征识别 与代谢失活相关的可能性 设计具有最佳作用持续时间的高活性分子。 将合成化合物的结构特征与其影响联系起来 血小板反应应允许解释人血 血小板反应模式方面的化学参数，并以'罚款- 将分子片段调整到最佳活性。

This project is aimed at developing novel synthetic compounds capable of stabilizing platelet membranes. One of the major thrusts is directed at aiding individuals especially predisposed to thromboembolic complicating resulting from their blood's exposure to biomaterials like implanted prosthetic devices and extracorporeal equipment. In this proposal, novel molecular entities will be obtained using a three-pronged approach: (i) because of the importance of enantioselectivity in drug action, each of the 3 most active compounds from their previous investigation will be resolved into its 3 stereoisomers. The individual enantiomers and diastereomers will be tested for their inhibitory effects on human blood platelet aggregation in vitro, induced by human alpha-thrombin, collagen, and epinephrine. (ii) Racemic analogues of the 3 compounds will be synthesized in order to extend their duration of action, and (iii) hydrophbiaity and electron density will be optimized in structural components not previously examined. Compounds showing reasonable potency in preliminary screening will be evaluated for their effects in vitro, (a) on cytosolic ionized calcium ([Ca. 2+]) concentrations, (b) on levels of platelet factor 4 (PF-4), platelet factor 3 (PF-3) and serotonin, and (c) for acute toxicity in vivo, in mice. In cooperation with Dr. Larry V. McIntire, at Rice University, the impact of selected compounds will be studied on the kinetics of human blood platelet adhesion and thrombus growth effected by collagen and biomaterials in his parallel plate flow chamber system. One or two highly active and least toxic compounds will be tested for platelet aggregation inhibitory activity, ex vivo, in dogs. The pharmacokinetics of the same compounds will be evaluated in mice and dogs, and bioavailibility in dogs. Structure of metabolites found in urine will be established using HPLC-MS. Due to the chiral environment of many biological systems, delineation of the enantio-selectivity of these synthetic compounds is expected to uncover increased antithrombotic potency which, at the same time, could register lesser toxicity. Identification of the structural features associated with metabolic inactivation would provide leads to the eventual design of highly active molecules with optimal duration of action. Relating structural features of the synthetic compounds to their influence on thrombocyte response should permit interpretation of human blood platelet response patterns in terms of chemical parameters, and to 'fine- tune' molecular segments toward optimal activity.