2. Academic Validation
  3. Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration

Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration

  • J Med Chem. 2025 Feb 27;68(4):4672-4693. doi: 10.1021/acs.jmedchem.4c02751.
François P Bischoff 1,  Sven Van Brandt 1,  Marcel Viellevoye 1,  Michel De Cleyn 1,  Michel Surkyn 1,  Rodrigo J Carbajo 2,  Maria Dominguez Blanco 1,  Berthold Wroblowski 1,  Nathan K Karpowich 3,  Ruth A Steele 3,  Celine Schalk-Hihi 3,  Robyn Miller 3,  David Duda 3,  Paul Shaffer 3,  Scott Ballentine 3,  Sirak Simavorian 4,  Brian Lord 4,  Robert A Neff 4,  Pascal Bonaventure 4,  Harrie J M Gijsen 1
Affiliations

Affiliations

  • 1 Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • 2 Janssen Research & Development, Janssen Cilag, Calle Jarama 75, 45007 Toledo, Spain.
  • 3 Janssen Research & Development, LLC, 1400 McKean Road (Welsh Road), Spring House, Pennsylvania 19477, United States.
  • 4 Janssen Research & Development, LLC, 3210 Merryfield Row, La Jolla, California 92121, United States.
PMID: 39960408 DOI: 10.1021/acs.jmedchem.4c02751
Abstract

N-Methyl-d-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The TCN-201 derivatives MPX-004 and MPX-007 are potent and selective for GluN2A receptors, yet their physical properties limit their in vivo utility. In this study, we optimized the MPX-004/MPX-007 scaffold by modifying the linker region between the distal halogenated aromatic ring and the central pyrazine nucleus, resulting in the identification of potent and selective compounds with improved drug-like properties. Notably, compound 1 was used to develop the first GluN2A NAM-based radioligand, and compound 11 showed improved pharmacokinetics and dose-dependent receptor occupancy in vivo. Thus, we provide an array of powerful new tools for the study of GluN2A receptors.

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