Discovery of N-(2-hydroxy-2-aryl-cyclohexyl) substituted spiropiperidines as GlyT1 antagonists with improved pharmacological profile

Simona M Ceccarelli; Emmanuel Pinard; Henri Stalder; Daniela Alberati

doi:10.1016/j.bmcl.2005.09.067

Discovery of N-(2-hydroxy-2-aryl-cyclohexyl) substituted spiropiperidines as GlyT1 antagonists with improved pharmacological profile

Bioorg Med Chem Lett. 2006 Jan 15;16(2):354-7. doi: 10.1016/j.bmcl.2005.09.067. Epub 2005 Oct 21.

Authors

Simona M Ceccarelli¹, Emmanuel Pinard, Henri Stalder, Daniela Alberati

Affiliation

¹ F. Hoffmann-La Roche Ltd, Pharmaceutical Division Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. simona_m.ceccarelli_grenz@roche.com

PMID: 16246561
DOI: 10.1016/j.bmcl.2005.09.067

Abstract

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.

MeSH terms

Binding Sites
Drug Evaluation, Preclinical
Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Humans
In Vitro Techniques
Molecular Conformation
Narcotic Antagonists
Nociceptin Receptor
Piperidines* / chemistry
Piperidines* / classification
Piperidines* / pharmacology
Receptors, Opioid
Receptors, Opioid, mu / antagonists & inhibitors
Spiro Compounds* / chemistry
Spiro Compounds* / classification
Spiro Compounds* / pharmacology
Structure-Activity Relationship

Substances

Glycine Plasma Membrane Transport Proteins
Narcotic Antagonists
Piperidines
Receptors, Opioid
Receptors, Opioid, mu
SLC6A5 protein, human
SLC6A9 protein, human
Spiro Compounds
Nociceptin Receptor
OPRL1 protein, human