Discovery of Pyrazolo[1,5-a]pyrazin-4-ones as Potent and Brain Penetrant GluN2A-Selective Positive Allosteric Modulators Reducing AMPA Receptor Binding Activity

• Published in: Bioorganic & medicinal chemistry 2022-02, Vol.56, p.116576-116576, Article 116576
• Main Authors: Sakurai, Fumie, Yukawa, Takafumi, Kina, Asato, Murakami, Masataka, Takami, Kazuaki, Morimoto, Sachie, Seto, Masaki, Kamata, Makoto, Yamashita, Tohru, Nakashima, Kosuke, Narita, Naohiro, Bettini, Ezio, Ugolini, Annarosa, Corsi, Mauro, Hasui, Tomoaki
• Format: Article
• Language: English
• Subjects: Administration, Oral; Allosteric Regulation - drug effects; Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR); Animals; Binding Sites - drug effects; Brain - metabolism; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; GluN2A; Injections, Intravenous; Long-term potentiation (LTP); Male; Molecular Docking Simulation; Molecular Structure; N-methyl-d-aspartate receptor (NMDAR); NR2A; Positive allosteric modulator; Pyrazolo[1,5-a]pyrazin-4-one; Rats; Rats, Sprague-Dawley; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116576

[Display omitted] N-Methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has recently attracted attention as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy. In the present study, we developed potent and brain-penetrable GluN2A-selective positive allosteric modulators. Lead compound 2b was generated by scaffold hopping of hit compound 1, identified from the internal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-focused compound library through a high-throughput screening campaign. Subsequent optimization of the lead compound, including a structure-based drug design approach, resulted in the identification of a potent GluN2A PAM (R)-9, which possessed high selectivity against both subtypes of AMPAR and NMDAR. Furthermore, (R)-9 significantly enhanced long-term potentiation in the rat hippocampus 24 h after oral administration, indicating that this molecule is a potentially useful in vivo pharmacological tool for treating psychiatric diseases.