Discovery of N-(2-hydroxy-2-aryl-cyclohexyl) substituted spiropiperidines as GlyT1 antagonists with improved pharmacological profile.
During SAR exploration of N-(2-aryl-cyclohexyl) substituted spiropiperidine as GlyT1 inhibitors, it was found that introduction of an hydroxy group in position 2 of the cyclohexyl residue considerably improves the pharmacological profile. In particular, reduction of the binding affinity at the nociceptin/orphanin FQ peptide and the mu opioid receptors was achieved.
Ceccarelli
Simona M
SM
F. Hoffmann-La Roche Ltd, Pharmaceutical Division Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. simona_m.ceccarelli_grenz@roche.com
Pinard
Emmanuel
E
Stalder
Henri
H
Alberati
Daniela
D
D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D008968:Molecular Conformation; D009292:Narcotic Antagonists; D010880:Piperidines / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D013141:Spiro Compounds / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
D050487:Glycine Plasma Membrane Transport Proteins; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C493271:SLC6A5 protein, human; C493268:SLC6A9 protein, human; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human