2. Academic Validation
  3. Synthesis of AC1903 analogs as potent transient receptor potential canonical channel 4/5 inhibitors and biological evaluation

Synthesis of AC1903 analogs as potent transient receptor potential canonical channel 4/5 inhibitors and biological evaluation

  • Bioorg Med Chem. 2022 Aug 15;68:116853. doi: 10.1016/j.bmc.2022.116853.
Lili Chen 1,  Zhuang Zhang 2,  Hongtao Tian 3,  Shan Jiang 2,  Yunyun Ji 2,  Mengru Liu 2,  Jianhua Shen 3,  Zhengyu Cao 4,  Kai Wang 5
Affiliations

Affiliations

  • 1 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; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 2 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of TCM Pharmacology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 639 Long Mian Road, Nanjing, Jiangsu 211198, 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 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of TCM Pharmacology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 639 Long Mian Road, Nanjing, Jiangsu 211198, China. Electronic address: [email protected].
  • 5 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].
PMID: 35653869 DOI: 10.1016/j.bmc.2022.116853
Abstract

Transient receptor potential canonical (TRPC) channels are a class of non-selective cation channels expressed in a variety of tissues and organ systems where they functionally regulate physiological and pathological processes. TRPC5 has been shown to be a promising target for focal segmental glomerulosclerosis treatment. In this study, we report the synthesis and biological evaluation of a novel series of benzimidazole-based TRPC5 inhibitors. One compound, 8b, is 100-fold more potent than the parent compound, AC1903, in the suppression of TRPC5 channel activity. Interestingly, both AC1903 and 8b also suppressed TRPC4 channel activity with similar potency. Compound 8b also significantly blunts protamine sulfate-induced reorganization of podocyte Cytoskeleton, interleukin (IL)-17-induced cell proliferation, and the expression of proinflammatory mediators in human keratinocyte HaCaT cells.

Keywords

AC1903; FSGS; Inflammation; Keratinocyte; Podocyte; Proliferation; TRPC5.

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