Discovery of 4-substituted-8-(2-hydroxy-2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one as a novel class of highly selective GlyT1 inhibitors with improved metabolic stability.


:A novel class of 4-aryl-8-(2-hydroxy-2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1- ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu-opioid receptor as well as the Nociceptin/Orphanin FQ peptide (NOP) receptor. In particular these novel compounds 4 as well as the 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one 3 show improved metabolic stability and pharmacokinetic profiles in rodents compared to previous triazaspiropiperidine series 1 and 2. We have also identified within these diazaspiropiperidine series a key relationship between reducing basicity of the piperidine nitrogen and reducing hERG affinity.


Bioorg Med Chem Lett


Alberati D,Hainzl D,Jolidon S,Krafft EA,Kurt A,Maier A,Pinard E,Thomas AW,Zimmerli D




Has Abstract


2006-08-15 00:00:00














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    journal_title:Bioorganic & medicinal chemistry letters

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    journal_title:Bioorganic & medicinal chemistry letters

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    pub_type: 杂志文章


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