In 2016,Volgraf, Matthew; Sellers, Benjamin D.; Jiang, Yu; Wu, Guosheng; Ly, Cuong Q.; Villemure, Elisia; Pastor, Richard M.; Yuen, Po-wai; Lu, Aijun; Luo, Xifeng; Liu, Mingcui; Zhang, Shun; Sun, Liang; Fu, Yuhong; Lupardus, Patrick J.; Wallweber, Heidi J. A.; Liederer, Bianca M.; Deshmukh, Gauri; Plise, Emile; Tay, Suzanne; Reynen, Paul; Herrington, James; Gustafson, Amy; Liu, Yichin; Dirksen, Akim; Dietz, Matthias G. A.; Liu, Yanzhou; Wang, Tzu-Ming; Hanson, Jesse E.; Hackos, David; Scearce-Levie, Kimberly; Schwarz, Jacob B. published 《Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design》.Journal of Medicinal Chemistry published the findings.Electric Literature of C4H3F3N2 The information in the text is summarized as follows:
The N-methyl-D-aspartate receptor (NMDAR) is a Na+ and Ca2+ permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate. NMDARs are critical to synaptic signaling and plasticity, and their dysfunction has been implicated in a number of neurol. disorders, including schizophrenia, depression, and Alzheimer’s disease. Herein we describe the discovery of potent GluN2A-selective NMDAR pos. allosteric modulators (PAMs) starting from a high-throughput screening hit. Using structure-based design, we sought to increase potency at the GluN2A subtype, while improving selectivity against related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The structure-activity relationship of channel deactivation kinetics was studied using a combination of electrophysiol. and protein crystallog. Effective incorporation of these strategies resulted in the discovery of GNE-0723 (46), a highly potent and brain penetrant GluN2A-selective NMDAR PAM suitable for in vivo characterization. The results came from multiple reactions, including the reaction of 3-(Trifluoromethyl)-1H-pyrazole(cas: 20154-03-4Electric Literature of C4H3F3N2)
3-(Trifluoromethyl)-1H-pyrazole(cas: 20154-03-4) belongs to pyrazoles. Pyrazole derivatives have been reported to exhibit a wide range of applications in medicinal chemistry and pharmacology. A large number of drugs incorporating pyrazole structure have been utilized as partial agonists for nicotinic acid receptors, antidepressants, antimicrobial agents, antiviral agents, and antifungal agents solely or along with the combination of other structural motifs.Electric Literature of C4H3F3N2
Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics