Exploring Five-Membered S -Heterocyclic Scaffolds As Novel CaMKIIα Ligands Targeting the Hub Domain

The Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a brain-relevant kinase involved in long-term potentiation and synaptic plasticity. In continuation of our efforts exploiting the CaMKIIα hub domain representing the high-affinity target of γ-hydroxybutyrate (GHB), we herein report a study on five-membered heterocycles related to 2-(2,6-dichlorophenyl)thiazole-4-carboxylic acid (PTCA), a low nanomolar-affinity ligand for the CaMKIIα hub domain. To explore the chemical scaffold without adversely affecting physicochemical parameters, we expanded the diversity of compounds by introducing a higher degree of saturation and chirality. A distinct preference for the presence and positioning of the sulfur atom in relation to the 4-carboxylic acid was observed together with stereoselective recognition patterns. The midnanomolar-affinity ligands 2 and 3a showed good cellular permeability which is vital for in vivo studies, and importantly, no efflux transporter substrate effect was observed.