Structure Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated, e.g. as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity towards the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby S-configuration on both generally exerting the highest activity and selectivity on DAT. The representative compound of this series was further characterized by in silico, in vitro and in vivo studies that have demonstrated bot...