Design and synthesis of 6-methylpyridin-2-one derivatives as novel and potent GluN2A positive allosteric modulators for the treatment of cognitive impairment. (1st February 2023)

• Record Type: Journal Article
• Authors: Yukawa, Takafumi; Yamashita, Tohru; Imaeda, Toshihiro; Kakei, Hiroyuki; Hashizume, Shogo; Nakamura, Minoru; Daini, Masaki; Okabe, Atsutoshi; Nakashima, Kosuke; Harada, Akina; Narita, Naohiro; Bettini, Ezio; Ugolini, Annarosa; Corsi, Mauro; Hasui, Tomoaki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 79(2023)
• Publication Date: 2023-02-01
• Subjects: N-methyl-D-aspartate receptor (NMDAR) -- GluN2A positive allosteric modulator (PAM) -- 6-methylpyridin-2-one -- Long-term potentiation (LTP); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117150
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: N -Methyl-D-aspartate receptors (NMDARs) are key regulators of synaptic plasticity in the central nervous system. Potentiation of NMDARs containing GluN2A subunit has been recently recognized as a promising therapeutic approach for neurological disorders. We identified a novel series of GluN2A positive allosteric modulator (PAM) with a pyridin-2-one scaffold. Initial lead compound 1 was discovered through in silico -based screening of virtual ligands with various monocyclic scaffolds. GluN2A PAM activity was increased by introduction of a methyl group at the 6-position of the pyridin-2-one ring and a cyano group in the side chain. Modification of the aromatic ring led to the identification of potent and brain-penetrant 6-methylpyridin-2-one 17 with a negligible binding activity for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Oral administration of 17 significantly enhanced rat hippocampal long-term potentiation (LTP). Thus, 17 would be a useful in vivo pharmacological tool to investigate complex NMDAR functions for the discovery of therapeutics toward diseases associated with NMDAR dysfunction