Baoxue Yang, MD, PhD | Peking University; Min Li, PhD; Yue Xu, PhD; Shuyuan Wang, PhD; Hang Zhang, MS; Yi Ying, MS; Nannan Li, MS
Competition Sponsor: Chinese Academy of Medical Sciences
Awardee Year: 2022
Previous studies of our group have shown that urea transporters (UT) play a very important role in the mechanism of renal urinary concentration. The inhibition of UT activity can block the intrarenal urea cycle, reduce capacity of urine concentration, and produce urea-selective diuresis. This project intends to establish the syndrome of inappropriate antidiuretic hormone secretion (SIADH) model, aortic constriction induced heart failure model and bile duct ligation induced cirrhosis ascites model, to explore the therapeutic effect of UT inhibitors on hyponatremia and its mechanism. Then carry out systematic preclinical pharmacodynamic and pharmacokinetic studies on this new diuretic, and confirm the target using UR knockout animal models. The final experimental results will support the scientific hypothesis that UT inhibitors can be used as new medication for hyponatremia. Also, non-clinical research reports will be generated for investigational new drug application. Our group found the first UT-specific inhibitor with oral diuretic activity-diarylamide compound S3-F (human UT IC50=0.08 μM), with diuretic effect (rat urine volume increased by 2 times, osmotic pressure decreased by 10 times, diuretic effect lasted for 8 hours), without affecting excretion of Na+, K+ and Cl-, less toxic side effects (high oral doses in mice do not show toxicity). The preparation process of S3-F is mature (6 steps, with an overall yield of 25%~30%, and the process can be scaled up for production). S3-F is expected to be developed into a First-in-class novel diuretic without affecting electrolyte balance for the treatment of hyponatremia.
To learn more about this proposal, email healthylongevity@nas.edu.