Negative allosteric modulators of NMDA receptors with GluN2B subunit: synthesis of β-aminoalcohols by epoxide opening and subsequent rearrangement

Abstract

In order to obtain novel antagonists of GluN2B subunit containing NMDA receptors, aryloxiranes were opened with benzylpiperidines. Phenyloxiranes 6 and (indazolyl)oxirane 15 were opened regioselectively at the position bearing the aryl moiety. Reaction of the resulting β-aminoalcohols 7 and 16 with carboxylic acids under Mitsunobu conditions (DIAD, PPh₃) led to rearrangement and after ester hydrolysis to the regioisomeric β-aminoalcohols 9 and 18. This strategy allows the synthesis of amino-ifenprodil 12 as well using phthalimide in the Mitsunobu reaction. Unexpectedly, the isomeric (indazolyl)oxirane 21 reacted with benzylpiperidines to afford both regioisomeric β-aminoalcohols 22 and 23. In radioligand receptor binding studies, the indazolyl derivative 18a, which can be regarded as indazole bioisostere of ifenprodil, showed high GluN2B affinity (K_i = 31 nM). Replacement of the benzylic OH moiety of ifenprodil by the NH₂ moiety in amino-ifenprodil 12 also resulted in low nanomolar GluN2B affinity (K_i = 72 nM). In TEVC experiments, 18a inhibited the ion flux to the same extent as ifenprodil proving that the phenol of ifenprodil can be replaced bioisosterically by an indazole ring maintaining affinity and inhibitory activity. Whereas 10-fold selectivity was found for the ifenprodil binding site over σ₁ receptors, only low preference for the GluN2B receptor over σ₂ receptors was detected. The log D_7.4 value of 18a (log D_7.4 = 2.08) indicates promising bioavailability.