4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: Design, synthesis and structure–activity relationships

• Published in: Bioorganic & medicinal chemistry letters 2009-05, Vol.19 (10), p.2829-2834
• Main Authors: Fish, Paul V., Andrews, Mark D., Jonathan Fray, M., Stobie, Alan, Wakenhut, Florian, Whitlock, Gavin A.
• Format: Article
• Language: English
• Subjects: 3-Piperidine; 3-Pyrrolidine; 4-Piperidine; Adrenergic Uptake Inhibitors - chemical synthesis; Adrenergic Uptake Inhibitors - chemistry; Adrenergic Uptake Inhibitors - pharmacokinetics; Animals; Biological and medical sciences; Drug Design; Dual SNRI; Medical sciences; Miscellaneous; Monoamine reuptake inhibitor; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Norepinephrine - metabolism; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacokinetics; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacokinetics; Rats; Selective NRI; Selective SRI; Serotonin - metabolism; Serotonin Uptake Inhibitors - chemical synthesis; Serotonin Uptake Inhibitors - chemistry; Serotonin Uptake Inhibitors - pharmacokinetics; Stereoisomerism; Structure-Activity Relationship; Triple SNDRI
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.03.090

[(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. 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.