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

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 (SAR) 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 (PK) and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid (CSF) glycine biomarker model in both rodents and non-human primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC)

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)

Lead Optimization toward Proof-of-Concept Tools for Huntington’s Disease within a 4‑(1<i>H</i>‑Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors

Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, <b>9t</b> was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound <b>9t</b> was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole