Synthesis and Biological Evaluation of <i>N</i>‑((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter‑1

We previously disclosed the discovery of rationally designed <i>N</i>-((1-(4-(propylsulfonyl)­piperazin-1-yl)­cycloalkyl)­methyl)­benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues <b>10</b> and <b>11</b>. We describe herein further structure–activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent <i>in vitro</i> GlyT-1 potency and selectivity, favorable ADME and <i>in vitro</i> pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-<b>67</b> exhibited robust <i>in vivo</i> activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-<b>67</b> significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC)