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)

J Med Chem. 2010 Jun 10;53(11):4511-21. doi: 10.1021/jm100053t.

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.

MeSH terms

  • Animals
  • Cell Line
  • Cyclic S-Oxides / chemical synthesis
  • Cyclic S-Oxides / chemistry*
  • Cyclic S-Oxides / pharmacokinetics
  • Cyclic S-Oxides / pharmacology*
  • Drug Discovery / methods*
  • Female
  • Humans
  • Male
  • Neurotransmitter Uptake Inhibitors / chemical synthesis
  • Neurotransmitter Uptake Inhibitors / chemistry*
  • Neurotransmitter Uptake Inhibitors / pharmacokinetics
  • Neurotransmitter Uptake Inhibitors / pharmacology*
  • Norepinephrine / metabolism*
  • Rats
  • Structure-Activity Relationship
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / chemistry*
  • Thiadiazoles / pharmacokinetics
  • Thiadiazoles / pharmacology*

Substances

  • 4-(3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol
  • Cyclic S-Oxides
  • Neurotransmitter Uptake Inhibitors
  • Thiadiazoles
  • benzo-1,2,3-thiadiazole
  • Norepinephrine