4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: design, synthesis and structure-activity relationships.
Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.
Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Kent, UK. paul.fish@pfizer.com
Paul V
PV
Fish
Mark D
MD
Andrews
M
M
Jonathan Fray
Alan
A
Stobie
Florian
F
Wakenhut
Gavin A
GA
Whitlock
D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D015195:Drug Design; D009638:Norepinephrine / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018759:Adrenergic Uptake Inhibitors; D009638:Norepinephrine; D010880:Piperidines; D011759:Pyrrolidines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors