Thiazole-Based σ₁ Receptor Ligands: Diversity by Late-Stage C-H Arylation of Thiazoles, Structure-Affinity and...

Spirocyclic thiophene derivatives represent promising σ₁ ligands with high σ₁ affinity and selectivity over the σ₂ subtype. To increase ligand efficiency, the thiophene ring was replaced bioisosterically by a thiazole ring, and the pyran ring was opened. Late-stage diversification by regioselective C-H arylation of thiazoles 9 a-c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to σ₁ affinity, σ₁ /σ₂ selectivity, lipophilicity (logD_7.4 ), lipophilicity-corrected ligand efficiency (LELP), and molecular target interactions. The most promising candidates were pyridyl-substituted thiazole derivatives 33 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-3-yl)thiazole) and 34 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-4-yl)thiazole), possessing low-nanomolar σ₁ affinity (K_i =1.3 and 1.9 nm), high σ₁ /σ₂ selectivity (>1500-fold), low lipophilicity (logD_7.4 =1.8) and very good ligand efficiency (LELP=5.5), indicating promising pharmacodynamics and pharmacokinetics. Molecular simulation studies, including docking and deconvolution of the free binding energy into its major components, led to decreased hydrophobic stabilization of pyridyl derivatives 33 c and 34 c, which was compensated by lower desolvation energy.