A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure-activity relationships.
A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.
Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USA. lvanorden@theravance.com
Lori Jean
LJ
Van Orden
Priscilla M
PM
Van Dyke
D Roland
DR
Saito
Timothy J
TJ
Church
Ray
R
Chang
Jacqueline A M
JA
Smith
William J
WJ
Martin
Sarah
S
Jaw-Tsai
Eric L
EL
Stangeland
D000818:Animals; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006801:Humans; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D009638:Norepinephrine; D011759:Pyrrolidines; D017367:Selective Serotonin Reuptake Inhibitors