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 as potential
therapeutics against cocaine addiction and for cognitive enhancement.
Our continuous effort to find modafinil analogues with higher inhibitory
activity on and selectivity toward 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 the S-configuration
on both generally exerted 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 both safety and efficacy
profile of this compound class.