Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.
Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China; Henan Engineering Research Center for Application and Translation of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China.
Biomed Pharmacother. 2024 Oct;179:117329. doi: 10.1016/j.biopha.2024.117329. Epub 2024 Aug 24.
ZCL-278 is a selective small molecule specifically inhibiting the Cdc42-intersectin interaction, yet its in-vivo pharmacokinetic and pharmacodynamic properties against renal diseases had not been determined. Thus, our study explored the absorption, distribution and excretion of ZCL-278 as well as its pharmacological efficacy against chronic kidney disease (CKD). With the optimized detection method, absolute oral bioavailability of ZCL-278 was determined as 10.99 % in male and 17.34 % in female rats. ZCL-278 was rapidly and abundantly distributed in various tissues, especially the kidney and heart, while few excreted through urine and feces. In the adenine-induced CKD mice, the increased plasma creatinine and urea, the decreased body weight as well as the renal pathological alterations, including vacuolization of renal tubular epithelial cells, granular degeneration, cell flattening, luminal dilation, and cylindruria, were significantly ameliorated after ZCL-278 administration. Moreover, ZCL-278 could also reverse the increased intensities of renal inflammation and fibrosis in the CKD mice. These results clarified the pharmacokinetics of ZCL-278 in rats and preliminarily indicated that ZCL-278 has favorable pharmacodynamic properties for CKD primed for lead development and optimization, warranting further drug development.
ZCL-278 是一种选择性的小分子，专门抑制 Cdc42- intersectin 相互作用，但它在体内治疗肾脏疾病的药代动力学和药效学特性尚未确定。因此，我们的研究探讨了 ZCL-278 的吸收、分布和排泄以及其对慢性肾脏病（CKD）的药效。通过优化的检测方法，确定 ZCL-278 在雄性和雌性大鼠中的绝对口服生物利用度分别为 10.99%和 17.34%。ZCL-278 在各种组织中分布迅速且丰富，特别是肾脏和心脏，而很少通过尿液和粪便排泄。在腺嘌呤诱导的 CKD 小鼠中，ZCL-278 给药后，血浆肌酐和尿素升高、体重下降以及肾脏病理改变，包括肾小管上皮细胞空泡化、颗粒变性、细胞扁平、管腔扩张和圆柱尿，均得到明显改善。此外，ZCL-278 还可以逆转 CKD 小鼠肾脏炎症和纤维化的增强程度。这些结果阐明了 ZCL-278 在大鼠中的药代动力学，并初步表明 ZCL-278 对 CKD 具有良好的药效学特性，为先导化合物的开发和优化提供了依据，值得进一步开发。
