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