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

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