Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 152, Issue -, Pages 235-252Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.04.045
Keywords
TRPM2; 2,3-Dihydroquinazolin-4(1H)-ones; Inhibitors; SAR; Virtual screening
Categories
Funding
- National Natural Science Foundation of China [NSFC 81573273, NSFC 81673279, NSFC 81571127, NSFC 21402171]
- Zhejiang Provincial Natural Science Foundation of China [LR16H090001]
Ask authors/readers for more resources
Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable cationic channel, plays critical roles in insulin release, cytokine production, body temperature regulation and cell death as a reactive oxygen species (ROS) and temperature sensor. However, few TRPM2 inhibitors have been reported, especially TRP-subtype selective inhibitors, which hampers the investigation and validation of TRPM2 as a drug target. To discover novel TRPM2 inhibitors, 3D similarity-based virtual screening method was employed, by which 2,3-dihydroquinazolin-4(1H)-one derivative H1 was identified as a TRPM2 inhibitor. A series of novel 2,3-dihydroquinazolin-4(1H)-one derivatives were subsequently synthesized and characterized. Their inhibitory activities against the TRPM2 channel were evaluated by calcium imaging and electrophysiology approaches. Some of the compounds exhibited significant inhibitory activity, especially D9 which showed an IC50 of 3.7 mu M against TRPM2 and did not affect the TRPM8 channel. The summarized structure-activity relationship (SAR) provides valuable insights for further development of specific TRPM2 targeted inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available