N-Benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amines as selective dual serotonin/noradrenaline reuptake inhibitors

Paul V Fish; M Jonathan Fray; Alan Stobie; Florian Wakenhut; Gavin A Whitlock

doi:10.1016/j.bmcl.2007.01.020

N-Benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amines as selective dual serotonin/noradrenaline reuptake inhibitors

Bioorg Med Chem Lett. 2007 Apr 1;17(7):2022-5. doi: 10.1016/j.bmcl.2007.01.020. Epub 2007 Jan 19.

Authors

Paul V Fish¹, M Jonathan Fray, Alan Stobie, Florian Wakenhut, Gavin A Whitlock

Affiliation

¹ Sandwich Chemistry Department, Pfizer Global Research and Development, Sandwich Labs, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.

PMID: 17267217
DOI: 10.1016/j.bmcl.2007.01.020

Abstract

A series of N-benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine monoamine reuptake inhibitors are described. Selective dual 5-HT and NA reuptake inhibition was achieved, and analogues with weak CYP2D6 inhibition, good human in vitro metabolic stability and wide ligand selectivity, such as 12b, were identified.

MeSH terms

Amines / chemistry
Chemistry, Pharmaceutical / methods*
Cytochrome P-450 CYP2D6 Inhibitors*
Drug Design
Ether-A-Go-Go Potassium Channels / chemistry
Hepatocytes / drug effects
Hepatocytes / metabolism
Humans
Inhibitory Concentration 50
Ligands
Microsomes / drug effects
Microsomes / metabolism
Models, Chemical
Molecular Conformation
Norepinephrine / antagonists & inhibitors*
Pyrrolidines / chemical synthesis*
Pyrrolidines / pharmacology
Selective Serotonin Reuptake Inhibitors / chemical synthesis*
Selective Serotonin Reuptake Inhibitors / chemistry
Selective Serotonin Reuptake Inhibitors / pharmacology

Substances

Amines
Cytochrome P-450 CYP2D6 Inhibitors
Ether-A-Go-Go Potassium Channels
KCNH1 protein, human
Ligands
Pyrrolidines
Serotonin Uptake Inhibitors
Norepinephrine