title: 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).
abstract: 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.
authors.affiliation: Chemical Sciences, Pfizer Global Research & Development, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. david.oneill@pfizer.com
authors.forename: David J
authors.initials: DJ
authors.lastname: O'Neill
authors.forename: Adedayo
authors.initials: A
authors.lastname: Adedoyin
authors.forename: Peter D
authors.initials: PD
authors.lastname: Alfinito
authors.forename: Jenifer A
authors.initials: JA
authors.lastname: Bray
authors.forename: Scott
authors.initials: S
authors.lastname: Cosmi
authors.forename: Darlene C
authors.initials: DC
authors.lastname: Deecher
authors.forename: Andrew
authors.initials: A
authors.lastname: Fensome
authors.forename: Jim
authors.initials: J
authors.lastname: Harrison
authors.forename: Liza
authors.initials: L
authors.lastname: Leventhal
authors.forename: Charles
authors.initials: C
authors.lastname: Mann
authors.forename: Casey C
authors.initials: CC
authors.lastname: McComas
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Sullivan
authors.forename: Taylor B
authors.initials: TB
authors.lastname: Spangler
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Uveges
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Trybulski
authors.forename: Garth T
authors.initials: GT
authors.lastname: Whiteside
authors.forename: Puwen
authors.initials: P
authors.lastname: Zhang
mesh_terms: 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*
chemical_list: 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