Titolo: Thiazole-based sigma-1 receptor ligands: Diversity by late-stage C-H arylation of thiazoles, structure affinity and selectivity relationships and molecular interactions
Abstract: Spirocyclic thiophene derivatives represent promising sigma-1 ligands with high sigma-1 affinity and selectivity over the sigma-2 subtype. In order 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 9a-c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to sigma-1 affinity, sigma-1/sigma-2 selectivity, lipophilicity (logD7.4), lipophilicity-corrected ligand efficiency (LELP) and molecular target interactions. The most promising candidates are the pyridyl substituted thiazole derivatives 33c and 34c possessing low nanomolar 1 affinity (Ki = 1.3 nM and 1.9 nM), high 1/2 selectivity (>1500-fold), low lipophilicity (logD7.4 = 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 reduced hydrophobic stabilization of the pyridyl derivatives 33c and 34c, which is compensated by lower desolvation energy.