Cao Xudong, Wang Peng, Zhao Wenchao, Yuan Haoxing, Hu Hongtao, Chen Ting, Zhang Yixiao, Ren Ying, Su Limin, Fu Kequan, Liu Hongli, Guo Dong
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu221004, China.
J Med Chem. 2023 Mar 9;66(5):3621-3634. doi: 10.1021/acs.jmedchem.3c00015. Epub 2023 Feb 2.
Vasopressin V receptors (VR) are a promising drug target for autosomal dominant polycystic kidney disease (ADPKD). As previous research demonstrated that the residence time of VR antagonists is critical to their efficacy in both ex vivo and in vivo models of ADPKD, we performed extensive structure-kinetic relationship (SKR) analyses on a series of benzodiazepine derivatives. We found that subtle structural modifications of the benzodiazepine derivatives dramatically changed their binding kinetics but not their affinity. Compound exhibited a residence time of 77 min, which was 7.7-fold longer than that of the reference compound tolvaptan (TVP). Accordingly, compound exhibited higher efficacy compared to TVP in an in vivo model of ADPKD. Overall, our study exemplifies a kinetics-directed medicinal chemistry effort for the development of efficacious VR antagonists. We envision that this strategy may also have general applicability in other therapeutic areas.
血管加压素V受体（VR）是常染色体显性多囊肾病（ADPKD）一个很有前景的药物靶点。由于先前的研究表明，VR拮抗剂的驻留时间对其在ADPKD的体外和体内模型中的疗效至关重要，我们对一系列苯二氮䓬衍生物进行了广泛的结构 - 动力学关系（SKR）分析。我们发现，苯二氮䓬衍生物的细微结构修饰极大地改变了它们的结合动力学，但没有改变它们的亲和力。化合物 表现出77分钟的驻留时间，这比参考化合物托伐普坦（TVP）的驻留时间长7.7倍。因此，在ADPKD的体内模型中，化合物 与TVP相比表现出更高的疗效。总体而言，我们的研究例证了一种用于开发有效VR拮抗剂的动力学导向药物化学研究。我们设想这种策略在其他治疗领域也可能具有普遍适用性。
