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 (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.