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.

中文翻译：

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具有记忆增强特性的新型和选择性甘氨酸转运蛋白-1（GlyT1）抑制剂的设计与合成

我们在这里报告了一系列有效的GlyT1抑制剂的鉴定和优化。的配体设计运动，利用公知的GlyT1抑制剂作为起始点导致的一系列新的吡咯并[3,4识别Ç ]吡唑酰胺（21 - 50）与体外效力良好。物理化学和体外ADME特性的后续优化产生了几种具有良好药代动力学特征的化合物。在单次口服10 mg / kg后，通过测量大鼠脑脊髓液（CSF）中甘氨酸的升高，证明了该系列中某些化合物对GlyT1的体内抑制作用。最终，优化了铅，化合物46在口服新颖剂量为0.1、1和3 mg / kg的大鼠新对象识别（NOR）试验中证明了体内功效。