Design and synthesis of 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one as a novel class of GlyT1 inhibitors: achieving selectivity against the mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors.
A novel class of 4-substituted-8-(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. A novel, straightforward and efficient synthetic strategy for the assembly of the target molecules is also presented.
Alberati
Daniela
D
Discovery Biology, F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Switzerland.
Ceccarelli
Simona M
SM
Jolidon
Synèse
S
Krafft
Eva A
EA
Kurt
Anke
A
Maier
Axel
A
Pinard
Emmanuel
E
Stalder
Henri
H
Studer
Deborah
D
Thomas
Andrew W
AW
Zimmerli
Daniel
D
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D018847:Opioid Peptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry; D011957:Receptors, Opioid / Q000737:chemistry; D013237:Stereoisomerism; D014965:X-Rays; D000097629:Nociceptin
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D050487:Glycine Plasma Membrane Transport Proteins; D018847:Opioid Peptides; D010455:Peptides; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; D000097629:Nociceptin; C493268:SLC6A9 protein, human