Thienopyrimidinone Derivatives as a GluN2B/C/D Biased, Positive Allosteric Modulator of the N‑Methyl‑d‑Aspartate Receptor

• Published in: Journal of medicinal chemistry Vol. 68; no. 9; pp. 9303 - 9322
• Main Authors: Fritzemeier, Russell G., Akins, Nicholas S., Arcoria, Paul J., Paladugu, Srinu, Ullman, Elijah Z., Allen, James, Sheikh, Rehan, Nocilla, Kelsey A., McDaniels, Ellington D., Coleman, Emanuel M., Antonoudiou, Pantelis, D’Erasmo, Michael P., Bartsch, Perry, Sharma, Savita K., Maguire, Jamie, Traynelis, Stephen F., Liotta, Dennis C.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.05.2025; Amer Chemical Soc
• Subjects: Allosteric Regulation - drug effects; Animals; Chemistry, Medicinal; HEK293 Cells; Humans; Life Sciences & Biomedicine; Mice; Pharmacology & Pharmacy; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacokinetics; Pyrimidinones - pharmacology; Rats; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - metabolism; Science & Technology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; INHIBITION; NMDA RECEPTORS; BRAIN; INTERNEURONS
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c02912

Positive allosteric modulators (PAMs) of the N-methyl-d-aspartate receptor (NMDAR) have been proposed as therapeutics in several neuropsychiatric indications, including schizophrenia, depression, cognitive dysfunction, and anxiety. In particular, GluN2D-containing NMDARs are highly expressed in inhibitory interneurons and are a target of interest for drug development. Toward that end, we describe our investigation into the GluN2-selective EU 1622 series of PAMs that enhance receptor efficacy, increase agonist potency, prolong deactivation time course, reduce single channel conductance, and limit calcium influx. Through SAR studies of the amide, aryl, and thiophene side chains, we identified analogues with submicromolar potency that preferentially potentiate GluN2B-, GluN2C-, and GluN2D-containing NMDARs. Elaboration of the thiophene side chain to block metabolism resulted in the discovery of EU 1622-240 (25b) with improved metabolic stability, oral bioavailability, and CNS penetration in rodents. Consequently, we present data with EU 1622-240 showing the promising properties of this series as a biased GluN2 potentiator.