Enantiomerically\nPure Indazole Bioisosteres of Ifenprodil\nand Ro 25-6981 as Negative Allosteric Modulators of NMDA Receptors\nwith the GluN2B Subunit

Administration of\nnegative allosteric modulators of GluN2B\nsubunit-containing\nNMDA receptors such as Ro 25-6981 (<b>1</b>) and ifenprodil\n(<b>2</b>) results in neuroprotective effects. In this study,\nthe phenol of <b>1</b> and <b>2</b> was replaced bioisosterically\nby an indazole to inhibit glucuronidation. The γ- and β-aminoalcohols <b>10</b> and <b>11</b> were prepared without installing a\nprotective 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\nreduction of ketones <b>7</b> and <b>9</b> followed by\nseparation of enantiomers. The analogously structured γ-aminoalcohol\n(1<i>S</i>,2<i>S</i>)-<b>10c</b> (Ro 25-6981\nbioisostere) and β-aminoalcohol (1<i>R</i>,2<i>R</i>)-<b>11c</b> (ifenprodil bioisostere) exhibited high\nGluN2B affinity (<i>K</i><sub><i>i</i></sub> =\n50 and 66 nM, respectively) and high to moderate inhibitory activity\nin 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\nacid, glucuronidation of <b>10</b> and <b>11</b> was not\nobserved.