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.
Alberati
Daniela
D
Discovery Biology, F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Basel, Switzerland.
Hainzl
Dominik
D
Jolidon
Synèse
S
Krafft
Eva A
EA
Kurt
Anke
A
Maier
Axel
A
Pinard
Emmanuel
E
Thomas
Andrew W
AW
Zimmerli
Daniel
D
D000818:Animals; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008956:Models, Chemical; D018847:Opioid Peptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D020033:Protein Isoforms; D011957:Receptors, Opioid / Q000737:chemistry; D000097629:Nociceptin
D051638:Ether-A-Go-Go Potassium Channels; D050487:Glycine Plasma Membrane Transport Proteins; D018847:Opioid Peptides; D010455:Peptides; D020033:Protein Isoforms; D011957:Receptors, Opioid; D000097629:Nociceptin; C092509:KCNH6 protein, human; C493268:SLC6A9 protein, human