Pyridyl-phenyl ether monoamine reuptake inhibitors: Impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity.
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.
Whitlock
Gavin A
GA
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. gavin.whitlock@pfizer.com
Fish
Paul V
PV
Fray
M Jonathan
MJ
Stobie
Alan
A
Wakenhut
Florian
F
D000588:Amines / Q000138:chemical synthesis / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D010647:Phenyl Ethers / Q000138:chemical synthesis / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000588:Amines; D009638:Norepinephrine; D010647:Phenyl Ethers; D011725:Pyridines; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors