ABSTRACT
We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. 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 in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo 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 (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).
Subject(s)
Benzamides/chemistry , Benzamides/pharmacology , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Glycine/cerebrospinal fluid , Glycine/metabolism , Glycine Plasma Membrane Transport Proteins/metabolism , Macaca fascicularis , Male , Methylation , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The design, synthesis, and structure-activity relationships (SAR) of a series of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1) are described. Optimization of the benzamide and central ring components of the core scaffold led to the identification of a GlyT-1 inhibitor that demonstrated in vivo activity in a rodent cerebral spinal fluid (CSF) glycine model.
