Design and Synthesis of Novel and Selective Glycine Transporter‑1 (GlyT1) Inhibitors with Memory Enhancing Properties

We report here the identification
and optimization of a novel series of potent GlyT1 inhibitors. A ligand
design campaign that utilized known GlyT1 inhibitors as starting points
led to the identification of a novel series of pyrrolo­[3,4-c]­pyrazoles amides (21–50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro
ADME properties produced several compounds with promising pharmacokinetic
profiles. In vivo inhibition of GlyT1 was demonstrated for select
compounds within this series by measuring the elevation of glycine
in the cerebrospinal fluid (CSF) of rats after a single oral dose
of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition
(NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.