Design, Synthesis And Biological Activity Evaluation Of Arginine Vasopressin V2Receptor Antagonists

Arginine vasopressin (AVP) plays an important role in the electrolyte balance ofhuman body. The disordered secretion of AVP may cause hyponatremia, syndrome ofinappropriate antidiuretic hormone secretion as well as congestive heart failure andother diseases, which would seriously damage human health. AVP V2receptorantagonists, such as tolvaptan and lixivaptan, are ideal drugs for these diseasesbecause that they could increase the excretion of free water without affecting themetabolism of electrolyte. However, several side effects were observed in the currentlaunched AVP V2receptor antagonists, which limited their use. Therefore thedevelopment new V2receptor antagonists with better efficacy and little side effectsis very important.Based on the summarizing of structure-activity relationship of V2receptorantagonists currently reported by literatures, common structural features of V2receptor antagonists were studied. By using the method of bioisosteres and so on,Two class, four series of300compounds with completely new structures weredesigned. The three-dimensional protein structure model of V2receptor was builtsuccessfully by homology modeling method. The designed compounds were screenedby virtual screening based on molecular docking and136compounds were slected tothe synthesis procedure.The synthetic process of tolvaptan and lixivaptan was optimized. Some of thesynthetic methods were innovative. The impurity in lixivaptan was isolated andsynthesized for the first time, and the byproducts in the synthetic process were alsoinvestigated. According to the synthesis methods of the positive control drugs, wedeveloped simple and reasonable routes to synthesize the136target compounds, ofwhich77compounds were chosen for biological activity evaluation. By detecting theaffinity effect to receptors and diuretic effect in rats, seven compounds A2-02, A2-43,A2-70, B1-39, B1-51, B1-60and B1-64with significant biological activities werescreened out successfully. The diuretic activities of B1-51and B1-64were even betterthan that of tolvaptan and lixivaptan. These compounds exhibited promising drug-likeproperties, and related preclinical studies are in progress.