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.

α2 Adrenoceptor: a Target for Neuropathic Pain Treatment

“…3). The Pfizer (Wyeth) Group has extensively investigated the field of norepinephrine reuptake inhibitors, producing a large number of studies [128][129][130][131][132][133][134]. Maintaining the 3-amino-2-hydroxy-1-phenylpropyl fragment as suitable template for CNS drug, they selected a series of scaffolds such as aniline [128], indole [129] and benzimidazole [130].…”

“…In particular, in the model of rat SNL, it significantly and dosedependent reversed the mechanical hyperalgesia at 3 and 10 mg/kg p.o., suggesting its potential use for the treatment of NP. The same research group successively focused their attention on the benzothiadiazole scaffold [133,134], synthesizing a series of derivatives C, evaluating structureactivity relationships and finally identifying two lead compounds, S-17b (WYE-103231, 4-[3-(2-fluorophenyl)-2,2-dioxo-2,3-dihydro-2λ 6 -benzo [1,2,5]thiadiazol-1-yl]-1methylamino-butan-2-ol) [133] and 10b (WYE-114152, 1-(2-fluorophenyl)-3-(2-morpholin-2-yl-ethyl)-1,3-dihydro-benzo[1,2,5]thiadiazole 2,2-dioxide) [134] with the best balance among potency as inhibitor of the NE transporter, selectivity over both 5-HT and DA transporter and pharmacokinetic profile. Compound S-17b (NE transporter inhibition IC 50 = 1 nM, NE transporter binding IC 50 = 6 nM) showed high to moderate clearance, high volume of distribution, a long half-life (3.2-6.3 h, depending on the species), a good brain penetration and finally a bioavailability from 41% to 100% [133].…”

Identification of a Novel Selective Serotonin Reuptake Inhibitor by Coupling Monoamine Transporter-Based Virtual Screening and Rational Molecular Hybridization

“…Even reports of ligand-based VS approaches are few (47, 48). Considering that MAT inhibitors serve to increase synaptic levels of monoamine neurotransmitter, modulation of postsynaptic monoamine receptors is another therapeutic avenue.…”

Radiosynthesis and first preclinical evaluation of the novel norepinephrine transporter pet-ligand [11C]ME@HAPTHI

“…Briefly, synthesis of (2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol followed the route described by Neill et al [20, 21]. For more details, see Additional file 1.…”

“…1). In general, the designed benzothidiazole dioxides exhibits excellent affinity and selectivity as well as slightly reduced flexibility compared to other previously published benzoimidazolones [20, 21]. Hence, these substances offer an ideal basis for the further development of novel NET ligands for PET imaging.

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