Discovery of N-alkyl-N-benzyl thiazoles as novel TRPC antagonists for the treatment of glioblastoma multiforme

  • Eur J Med Chem. 2024 Feb 5:265:116066. doi: 10.1016/j.ejmech.2023.116066.
Shanshan Wang  1 ,  Xiaoxue Li  2 ,  Yuemiao Hu  1 ,  Lin Wang  1 ,  Guangyao Lv  1 ,  Yuxin Feng  1 ,  Ziqiang Sun  2 ,  Zhengyu Cao  3 ,  Yi Liu  4 ,  Hongbo Wang  5
Affiliations
  • 1. Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
  • 2. School of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005, China.
  • 3. State Key Laboratory of Natural Medicines & Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 4. School of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005, China. Electronic address: [email protected].
  • 5. Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China. Electronic address: [email protected].
PMID: 38185057 DOI: 10.1016/j.ejmech.2023.116066
Abstract

Glioblastoma Multiforme represents a substantial clinical challenge. Transient receptor potential channel (TRPC) antagonists might provide new therapeutic options for this aggressive Cancer. In this study, a series of N-alkyl-N-benzoyl and N-alkyl-N-benzyl thiazoles were designed and prepared using a scaffold-hopping strategy and evaluated as TRPC6 antagonists. This resulted in the discovery of 15g, a potent TRPC antagonist that exhibited suitable inhibitory micromolar activities against TRPC3, TRPC4, TRPC5, TPRC6, and TRPC7 and displayed noteworthy anti-glioblastoma efficacy in vitro against U87 cell lines. In addition, 15g featured an acceptable pharmacokinetic profile and exhibited better in vivo potency (25 mg/kg/d) than the frontline therapeutic agent temozolomide (50 mg/kg/d) in xenograft models. Taken together, the TRPC antagonist 15g represents a promising lead compound for developing new anti-glioblastoma agents.

Keywords
Antiproliferative; Glioblastoma multiforme; In vivo efficacy; N-alkyl-N-benzyl thiazoles; TRPC antagonist.