Discovery of novel selective norepinephrine reuptake inhibitors: 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231).
Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.
O'Neill
David J
DJ
Chemical Sciences, Pfizer Global Research & Development, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. david.oneill@pfizer.com
Adedoyin
Adedayo
A
Alfinito
Peter D
PD
Bray
Jenifer A
JA
Cosmi
Scott
S
Deecher
Darlene C
DC
Fensome
Andrew
A
Harrison
Jim
J
Leventhal
Liza
L
Mann
Charles
C
McComas
Casey C
CC
Sullivan
Nicole R
NR
Spangler
Taylor B
TB
Uveges
Albert J
AJ
Trybulski
Eugene J
EJ
Whiteside
Garth T
GT
Zhang
Puwen
P
D000818:Animals; D002460:Cell Line; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
C550467:4-(3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol; D003499:Cyclic S-Oxides; D014179:Neurotransmitter Uptake Inhibitors; D013830:Thiadiazoles; C015700:benzo-1,2,3-thiadiazole; D009638:Norepinephrine