1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as Potent and Selective Norepinephrine Reuptake Inhibitors

Vu, A. T.; Cohn, Stephen T.; Zhang, Puwen; Kim, Callain Y.; Mahaney, Paige E.; Bray, Jeffrey D.; Johnston, Grace H.; Koury, Elizabeth J.; Cosmi, Scott; Deecher, Darlene C.; Smith, Valerie A.; Harrison, James; Leventhal, Liza; Whiteside, Garth T.; Kennedy, Jeffrey D.; Trybulski, Eugene J.

doi:10.1021/jm901559e

Cited by 24 publications

(19 citation statements)

References 61 publications

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“…As such, these data demonstrate that increased noradrenaline in the absence of effects on 5‐HT is sufficient for antidepressant and analgesic activity. This pre‐clinical profile is comparable to other potent and selective compounds from this class and series that have been profiled, albeit to a lesser extent, in pre‐clinical pain models (Vu et al. , 2009; Zhang et al.…”

Section: Discussionmentioning

confidence: 52%

WAY‐318068: a novel, potent and selective noradrenaline re‐uptake inhibitor with activity in rodent models of pain and depression

Whiteside¹,

Dwyer²,

Harrison³

et al. 2010

British J Pharmacology

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Background and purpose: Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity. Experimental approach: In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (Key results: WAY-318068 is a potent and effective inhibitor of the NET with a Ki of 8.7 nM in a binding assay, and an IC50 of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits. Conclusions and implications:Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.

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Section: Discussionmentioning

confidence: 52%

WAY‐318068: a novel, potent and selective noradrenaline re‐uptake inhibitor with activity in rodent models of pain and depression

Whiteside¹,

Dwyer²,

Harrison³

et al. 2010

British J Pharmacology

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“…(S, S)-reboxetine showed 130-fold higher affinity to hNET than (R, R)-reboxetine, and was reported as the predominant influence on reboxetine’s steady state pharmacological property 7 . Due to the existing deficiencies of currently marketed sNRIs (their delayed onset of action 8 and non- or partial-response 9 ), new strategies were applied to enhance drug efficacy by improving their metabolic and pharmacological properties 10 11 or by developing dual- and triple-acting antidepressants 12 . The binding mode shared by all approved and marketed sNRIs could contribute to the discovery of drug-like scaffold with enhanced efficacy 13 14 .…”

mentioning

confidence: 99%

Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

Zheng

Xue

Wang

et al. 2016

Sci Rep

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Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine’s enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.

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“…Substituted 3‐amino‐1,2‐diols are a characteristic structural unit present in numerous biologically active compounds, such as leukotriene antagonists,1 human carbonic anhydrase inhibitors,2 and anti‐inflammatory agents 3. Furthermore, 3‐amino‐1,2‐diols are also important synthetic intermediates of cardiovascular,4 antibacterial,5 and sedative agents,6 selective norepinephrine reuptake inhibitors,7 and drug candidates for the treatment of conditions that are ameliorated by monoamine reuptake 8. Most of these biologically important molecules are required to be virtually enantiopure (>99.8 % ee , < 0.1 % of the other enantiomer) for the pharmaceutical applications.…”

Section: Methodsmentioning

confidence: 99%

Tungsten‐Catalyzed Regio‐ and Enantioselective Aminolysis of trans‐2,3‐Epoxy Alcohols: An Entry to Virtually Enantiopure Amino Alcohols

Wang

Yamamoto

2014

Angewandte Chemie

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The first catalytic enantioselective aminolysis of trans‐2,3‐epoxy alcohols has been accomplished. This stereospecific ring‐opening process was efficiently promoted by a tungsten/bis(hydroxamic acid) catalytic system, furnishing various anti‐3‐amino‐1,2‐diols with excellent regiocontrol and high enantioselectivities (up to 95 % ee). Moreover, virtually enantiopure 3‐amino‐1,2‐diols could be obtained by the sequential combination of two reactions that both involve the use of a chiral catalyst.

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1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as Potent and Selective Norepinephrine Reuptake Inhibitors

Cited by 24 publications

References 61 publications

WAY‐318068: a novel, potent and selective noradrenaline re‐uptake inhibitor with activity in rodent models of pain and depression

WAY‐318068: a novel, potent and selective noradrenaline re‐uptake inhibitor with activity in rodent models of pain and depression

Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

Tungsten‐Catalyzed Regio‐ and Enantioselective Aminolysis of trans‐2,3‐Epoxy Alcohols: An Entry to Virtually Enantiopure Amino Alcohols

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