Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 61, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2022.128612
Keywords
TRPC5; Pyrroledione; FSGS; CKD
Categories
Funding
- Science and Technology Commission of Shanghai Municipality (STCSM) [19431900900]
- Youth Innovation Promotion Association, Chinese Academy of Sciences [2019282]
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica
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The synthesis and biological evaluation of a series of pyrroledione TRPC5 inhibitors has led to the discovery of compound 16g with subtype selectivity, showing improved inhibition of TRPC5 and enhanced protective effect against PS-induced podocyte injury in vitro. Compound 16g also demonstrated no cell death in primary cultured hepatocytes and immortalized podocytes in a preliminary toxicity assessment, suggesting its potential as a potent and safe inhibitor for studying the function of TRPC5.
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.
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