Enantiomerically Pure Indazole Bioisosteres of Ifenprodil and Ro 25-6981 as Negative Allosteric Modulators of NMDA Receptors with the GluN2B Subunit

J Med Chem. 2024 Nov 14;67(21):19678-19688. doi: 10.1021/acs.jmedchem.4c02035. Epub 2024 Oct 17.

Abstract

Administration of negative allosteric modulators of GluN2B subunit-containing NMDA receptors such as Ro 25-6981 (1) and ifenprodil (2) results in neuroprotective effects. In this study, the phenol of 1 and 2 was replaced bioisosterically by an indazole to inhibit glucuronidation. The γ- and β-aminoalcohols 10 and 11 were prepared without installing a protective group at the indazole ring using the ketone 6 as a common intermediate. All four stereoisomeric γ- and β-aminoalcohols 10 and 11 were obtained by diastereoselective reduction of ketones 7 and 9 followed by separation of enantiomers. The analogously structured γ-aminoalcohol (1S,2S)-10c (Ro 25-6981 bioisostere) and β-aminoalcohol (1R,2R)-11c (ifenprodil bioisostere) exhibited high GluN2B affinity (Ki = 50 and 66 nM, respectively) and high to moderate inhibitory activity in two-electrode voltage clamp experiments. The indazole bioisosteres 10 and 11 showed higher metabolic stability than 1. In the presence of uridinyldiphosphate activated glucuronic acid, glucuronidation of 10 and 11 was not observed.

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Humans
  • Indazoles* / chemical synthesis
  • Indazoles* / chemistry
  • Indazoles* / pharmacology
  • Mice
  • Phenols
  • Piperidines* / chemical synthesis
  • Piperidines* / chemistry
  • Piperidines* / pharmacology
  • Rats
  • Receptors, N-Methyl-D-Aspartate* / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate* / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Receptors, N-Methyl-D-Aspartate
  • NR2B NMDA receptor
  • Indazoles
  • ifenprodil
  • Piperidines
  • Ro 25-6981
  • Phenols