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

Zhuang Zhang; Lili Chen; Hongtao Tian; Mengru Liu; Shan Jiang; Jianhua Shen; Kai Wang; Zhengyu Cao

doi:10.1016/j.bmcl.2022.128612

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. Epub 2022 Feb 7.

Authors

Zhuang Zhang¹, Lili Chen², Hongtao Tian³, Mengru Liu¹, Shan Jiang¹, Jianhua Shen³, Kai Wang⁴, Zhengyu Cao⁵

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: kwang@simm.ac.cn.
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: zycao@cpu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Podocytes / drug effects
Podocytes / metabolism
Podocytes / pathology
Protamines
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship
TRPC Cation Channels / antagonists & inhibitors*
TRPC Cation Channels / metabolism

Substances

Protamines
Pyrroles
TRPC Cation Channels
TRPC5 protein, human