PAF受体拮抗剂芳氨酮衍生物分子设计合成药效学研究

Platelet-activating factor (PAF) which belongs to phospholipids generated from several inflammatory cells is a potent autacoid mediator. It binds to the corresponding receptor in the target cells and enkindles varied responses by G-protein-linking signal transduction. It has been suggested PAF was implicated in inflammation. In recent years PAF receptor has became one of the important target in the development of new anti-inflammatory drugs. In the worldwide more than 60 pharmaceutical companies or institutes commit oneself to search PAF antagonist candidates. Among those researches several candidates aim at therapy the inflammatory diseases. But no PAF antagonist has came into the market yet . Compound 96303 is a PAF antagonist which was designed, synthesized and screened by ourself. In this project 96303 as the lead compound were modified diversely. One hundred compounds which were divided into 3 types and subdivided into 8 sorts were synthesized. Those were screened by method of β-glucuronidase release. Six compounds among them as candidates were shown to have potent pharmacological effect. According to those results some informations about relationship of their structure and activity were obtained. Furthermore, It has been demonstrated that compound 0916 is a new structure chemicals by National Bureau of Knowledge Right. We are going to apply its chemical and pharmacological patent as soon as possible. On the bases of screening the effects of above candidates were increasingly investigated on the in vitro organ, tissue, cells, molecules and in vivo animal model levels. The results indicated that the candidates have strong antagonistic effect on PAF receptors and have significant inhibitory effect on the function of inflammatory cells (included neutrophils, macrophages and endothelial cells), such as chemotaxis, release of cytokine, production of superoxide anion, cells adhesion and expression of adhesion molecules and on inflammatory animal models. Moreover, The research about compound 0916 have been funded by National 863 project and Beijing new drug development plan.

血小板活化因子（PAF）是作用很强的炎性介质，近年其受体已成为新药设计的靶点。芳氨辔孕猩杓坪铣傻男陆峁筆AF受体拮抗剂。在体内外多种炎症过敏免疫模型上均有较强的活性。本项目拟以96303为先导物，通过计算机辅助分子设计、药化、药理的综合研究，期竦肞AF受体拮抗剂构效关系、受体可能结合位点的信息，找到1-2个可供开发的新药。