新型精氨酸加压素V2受体拮抗剂的设计与生物活性研究

目的 根据药物构效关系,设计合成出一系列结构新颖的V2受体拮抗剂,以期筛选出高效低毒的此类化合物,为进行下一步的临床前研究创造条件,为新药的创制奠定基础。方法 根据“me-too”的设计思路合成一定数量结构新颖的V2受体拮抗剂。通过核磁共振氢谱(¹H-NMR)、高分辨质谱(HRMS)等手段进行结构确证,并且测定了熔点、纯度等相关理化常数。通过表达人类V2受体的细胞模型和大鼠利尿模型进行生物活性评价。结果 设计合成出12个未见文献报道的目标化合物(A1~A12),以托伐普坦为阳性对照药,其中A6,A7,A11等化合物表现出较强的生物活性,并且具有作用持续时间更长的特点。结论 化合物结构设计合理,对进一步开展V2受体拮抗剂的结构改造及其药理毒理活性研究具有一定的参考价值。

Design and Biological Activity of Novel Arginine Vasopressin V2 Receptor Antagonists

OBJECTIVE To design and synthesize a series of novel V2 receptor antagonists according to the drug structure-activity relationship in order to screen out compounds with high efficacy and low toxicity and create conditions for preclinical research and lay foundation for the development of new drugs. METHODS A number of novel V2 receptor antagonists were synthesized according to the design idea of “me-too”. The structure was confirmed by ¹H-NMR and HRMS, and the physicochemical constants related to the melting point and purity were determined. Biological activity was evaluated by cell model expressing human V2 receptor and rat diuretic model. RESULTS Twelve novel structural compounds(A1-A12) were designed and synthesized, among which A6, A7, A11 and other compounds showed strong biological activity and a longer duration of action than the existing V2 receptor antagonists. CONCLUSION The reasonable structure design of the compound has certain reference value for the further research on the structure modification of V2 receptor antagonist and their pharmacological and toxicological activities.