Diastereoselective synthesis and structure-affinity relationships of s₁ receptor ligands with spirocyclic scaffold

Spirocyclic scaffolds play an increasing role in drug discovery as they define a rigid three-dimensional space to increase specific interactions with protein binding sites. Herein, a spirocyclic center was introduced into the lead compound 1 to rigidify its flexible benzylaminoethyl side chain. The key step of the synthesis was the reaction of different alpha,ss-unsaturated amides 6 and 13-16 with methyl acrylate in the presence of TBDMSOTf. DFT calculations explain the mechanism of this transformation as concerted Diels-Alder reaction (functionals B3LYP and TPSS) or double (aza)-Michael addition ( functionals PBE and wB97X-D). After separation of the diastereomeric spirocyclic products 8 and 17-20, LiAlH4 reduction provided the spirocyclic hydroxymethyl piperidines 21a,b-25a,b showing low nanomolar sigma 1 affinity (Ki < 100 nM). trans-Configured ligands (a-series) showed higher or equal sigma 1 affinity and higher selectivity over sigma 2 receptors and GluN2B-NMDA receptors than their cis-configured analogs (b-series). The additional hydroxymethyl moiety brings the logD(7.4) value in a promising range. The high s1 affinity (K-i = 3.6 nM) and the low lipophilicity result in the highest lipophilic ligand efficiency for the dispiro compound 23a (LLE = 6.0). The spirocyclic compounds reported herein and in particular the dispiro compound 23a demonstrate that ligands containing a large number of sp(3) C-atoms possess favorable pharmacological (sigma 1 receptor affinity, receptor selectivity) and physicochemical properties (logD(7.4) value) resulting in promising LLE.