Design, synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists.
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.
Dounay
Amy B
AB
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, United States. Amy.Dounay@pfizer.com
Barta
Nancy S
NS
Campbell
Brian M
BM
Coleman
Corey
C
Collantes
Elizabeth M
EM
Denny
Lynne
L
Dutta
Satavisha
S
Gray
David L
DL
Hou
Dongfeng
D
Iyer
Rathna
R
Maiti
Samarendra N
SN
Ortwine
Daniel F
DF
Probert
Al
A
Stratman
Nancy C
NC
Subedi
Rajendra
R
Whisman
Tammy
T
Xu
Wenjian
W
Zoski
Kim
K
D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010636:Phenols / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010636:Phenols; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C042329:phenoxy radical