Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP‐432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects

Sramek, John J.; Hardy, Larry W.; Bieck, P. R.; Zamora, Cynthia; Versavel, Mark; Kharidia, Jahnavi; Grinnell, Todd; Chen, Yu-Luan; Sullivan, Michael P.; Ding, Hong; Cutler, Neal R.

doi:10.1111/cns.12513

Cited by 2 publications

(3 citation statements)

References 41 publications

(46 reference statements)

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“…Recently, an exploratory biomarker study of 66 conducted at an MTD of 300 mg/day in healthy volunteers, with duloxetine (18) as the active control at a dose of 60 mg/day, was reported. 80 On day 14, 66 showed a t max of 4 h and t 1/2 of 18 h in CSF with a B/P ratio of 0.22, while the metabolite 117 showed a t max of 6 h and a t 1/2 of 32 h with a B/P ratio of 0.46. In CSF, both 66 and 18 increased NE and significantly reduced dihydroxyphenylglycol (DHPG), a metabolite of NE and biomarker for NET inhibition, relative to placebo, confirming NET inhibition.…”

Section: Neurosearch (Ns) Seriesmentioning

confidence: 94%

“…This is because in vitro assays do not adequately mimic the physiological environment of in vivo experiments, the latter being influenced by factors that include pharmacokinetic properties, blood–brain barrier permeability, and protein binding. This view is supported by the inconsistencies observed between in vitro and in vivo activities of existing antidepressants like 23 and investigational TRIs like 65 and SEP-228432 ( 66 ). , Hence, the relative contribution of individual transporter blockade needs to be carefully judged based on translating in vivo activity (for example, efficacy in the behavioral model like TST or FST) which, in turn, will reflect the effect on individual transporters. Impact of TRIs on individual transporters can be assessed by (a) microdialysis experiments, which indirectly evaluate elevation of individual monoamines, and (b) transporter occupancy, which assesses a direct effect based on target engagement.…”

Section: Tris/serotonin Norepinephrine Dopamine Reuptake Inhibitors (...mentioning

confidence: 99%

“…Replacing the dichlorophenyl of 66 with a 2-naphthyl group gave 118 , a change in structure that resulted in higher SERT activity but reduced DAT potency. Recently, an exploratory biomarker study of 66 conducted at an MTD of 300 mg/day in healthy volunteers, with duloxetine ( 18 ) as the active control at a dose of 60 mg/day, was reported . On day 14, 66 showed a t max of 4 h and t 1/2 of 18 h in CSF with a B/P ratio of 0.22, while the metabolite 117 showed a t max of 6 h and a t 1/2 of 32 h with a B/P ratio of 0.46.…”

Section: Discovery and Development Of Trismentioning

confidence: 99%

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Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

Subbaiah

2017

J. Med. Chem.

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Although first-line antidepressants offer therapeutic benefit, about 35% of depressed patients are not adequately treated, creating a large unmet medical need. These medicines mostly enhance the synaptic levels of serotonin and/or norepinephrine. Evidence from preclinical and clinical studies implicate dopamine hypofunction in the pathophysiology of depression. Triple reuptake inhibitors (TRIs), which elevate dopamine in addition to serotonin and norepinephrine, may demonstrate greater efficacy, with the reversal of anhedonia and improved tolerability. Medicinal chemistry efforts have resulted in more than 10 clinical candidates, although clinical candidates have failed to demonstrate superior efficacy compared to placebo or existing antidepressants. Hence, the successful development of future TRIs for depression will demand strong translational evidence, an optimal dosing regimen, and better tolerability. TRIs also hold therapeutic potential for other indications, with four candidates under clinical development for attention deficit hyperactivity disorder, binge eating disorder, cocaine addiction, obesity, and type 2 diabetes. Clinical studies have indicated a lower abuse potential for TRIs than psychostimulants.

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Section: Neurosearch (Ns) Seriesmentioning

confidence: 94%

Section: Tris/serotonin Norepinephrine Dopamine Reuptake Inhibitors (...mentioning

confidence: 99%

Section: Discovery and Development Of Trismentioning

confidence: 99%

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Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

Subbaiah

2017

J. Med. Chem.

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Major depressive disorder: hypothesis, mechanism, prevention and treatment

Cui,

Li,

Wang

et al. 2024

Sig Transduct Target Ther

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Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.

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Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP‐432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects

Abstract: CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.

Cited by 2 publications

References 41 publications

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

Major depressive disorder: hypothesis, mechanism, prevention and treatment

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