Pyridyl-phenyl ether monoamine reuptake inhibitors: Impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity

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

doi:10.1016/j.bmcl.2008.03.082

Pyridyl-phenyl ether monoamine reuptake inhibitors: Impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity

Bioorg Med Chem Lett. 2008 May 1;18(9):2896-9. doi: 10.1016/j.bmcl.2008.03.082. Epub 2008 Apr 8.

Authors

Gavin A Whitlock¹, Paul V Fish, M Jonathan Fray, Alan Stobie, Florian Wakenhut

Affiliation

¹ Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. gavin.whitlock@pfizer.com

PMID: 18417343
DOI: 10.1016/j.bmcl.2008.03.082

Abstract

A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted that potent dual SNRI activity was only achievable at c log P>3.5. The series was found to possess significant polypharmacology issues, and we concluded that this off-target promiscuity was related to lipophilicity.

MeSH terms

Amines / chemical synthesis
Amines / pharmacology*
Hepatocytes / drug effects*
Hepatocytes / metabolism
Humans
Inhibitory Concentration 50
Models, Chemical
Norepinephrine / antagonists & inhibitors*
Phenyl Ethers / chemical synthesis
Phenyl Ethers / pharmacology*
Pyridines / chemical synthesis
Pyridines / pharmacology*
Selective Serotonin Reuptake Inhibitors / chemical synthesis
Selective Serotonin Reuptake Inhibitors / pharmacology*
Serotonin 5-HT1 Receptor Antagonists*
Structure-Activity Relationship

Substances

Amines
Phenyl Ethers
Pyridines
Serotonin 5-HT1 Receptor Antagonists
Serotonin Uptake Inhibitors
Norepinephrine