2. Academic Validation
  3. Discovery of pyrroledione analogs as potent transient receptor potential canonical channel 5 inhibitors

Discovery of pyrroledione analogs as potent transient receptor potential canonical channel 5 inhibitors

  • Bioorg Med Chem Lett. 2022 Apr 1;61:128612. doi: 10.1016/j.bmcl.2022.128612.
Zhuang Zhang 1,  Lili Chen 2,  Hongtao Tian 3,  Mengru Liu 1,  Shan Jiang 1,  Jianhua Shen 3,  Kai Wang 4,  Zhengyu Cao 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 639 Long Mian Road, Nanjing, Jiangsu 211198, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: [email protected].
  • 5 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 639 Long Mian Road, Nanjing, Jiangsu 211198, China. Electronic address: [email protected].
PMID: 35143983 DOI: 10.1016/j.bmcl.2022.128612
Abstract

A deepening understanding of the relationship between transient receptor potential canonical channel 5 (TRPC5) and chronic kidney disease (CKD), has led to the emergence of several types of TRPC5 inhibitors displaying clear therapeutic effect. Herein, we report the synthesis and biological evaluation of a series of pyrroledione TRPC5 inhibitors, culminating in the discovery of compound 16g with subtype selectivity. Compared with GFB-8438, a potent TRPC5 inhibitor (Goldfinch Bio), compound 16g showed improved inhibition of TRPC5 and enhanced protective effect against protamine sulfates (PS)-induced podocyte injury in vitro. In addition, compound 16g did not induce cell death in primary cultured hepatocytes and immortalized podocytes in a preliminary toxicity assessment, indicating its utility as a potent and safe inhibitor for studying the function of TRPC5.

Keywords

CKD; FSGS; Pyrroledione; TRPC5.

Figures
Products