Work

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

Year: 2024

Type: article

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 (1 S,2 S )- 10c (Ro 25-6981 bioisostere) and β-aminoalcohol (1 R,2 R )- 11c (ifenprodil bioisostere) exhibited high GluN2B affinity ( K i = 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.4c02035