Design, synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists

Amy B Dounay; Nancy S Barta; Brian M Campbell; Corey Coleman; Elizabeth M Collantes; Lynne Denny; Satavisha Dutta; David L Gray; Dongfeng Hou; Rathna Iyer; Samarendra N Maiti; Daniel F Ortwine; Al Probert; Nancy C Stratman; Rajendra Subedi; Tammy Whisman; Wenjian Xu; Kim Zoski

doi:10.1016/j.bmcl.2009.12.023

Design, synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1114-7. doi: 10.1016/j.bmcl.2009.12.023. Epub 2009 Dec 6.

Authors

Amy B Dounay¹, Nancy S Barta, Brian M Campbell, Corey Coleman, Elizabeth M Collantes, Lynne Denny, Satavisha Dutta, David L Gray, Dongfeng Hou, Rathna Iyer, Samarendra N Maiti, Daniel F Ortwine, Al Probert, Nancy C Stratman, Rajendra Subedi, Tammy Whisman, Wenjian Xu, Kim Zoski

Affiliation

¹ Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, United States. Amy.Dounay@pfizer.com

PMID: 20031410
DOI: 10.1016/j.bmcl.2009.12.023

Abstract

Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.

Publication types

Comparative Study

MeSH terms

Adrenergic Uptake Inhibitors / chemical synthesis*
Adrenergic Uptake Inhibitors / metabolism
Adrenergic Uptake Inhibitors / pharmacology
Cell Line
Crystallography, X-Ray
Drug Design*
Drug Evaluation, Preclinical / methods
Humans
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Norepinephrine Plasma Membrane Transport Proteins / metabolism
Phenols / chemical synthesis
Phenols / metabolism
Phenols / pharmacology
Pyridines / chemical synthesis*
Pyridines / metabolism
Pyridines / pharmacology
Receptor, Serotonin, 5-HT1A / metabolism
Serotonin 5-HT1 Receptor Agonists*
Serotonin Receptor Agonists / chemical synthesis*
Serotonin Receptor Agonists / metabolism
Serotonin Receptor Agonists / pharmacology

Substances

Adrenergic Uptake Inhibitors
Norepinephrine Plasma Membrane Transport Proteins
Phenols
Pyridines
Serotonin 5-HT1 Receptor Agonists
Serotonin Receptor Agonists
Receptor, Serotonin, 5-HT1A
phenoxy radical