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Sanchez C.,Lundbeck Research United States Inc. | Reines E.H.,Lundbeck | Montgomery S.A.,University of London
International Clinical Psychopharmacology

It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), provide advantages in tolerability over antidepressants such as the tricyclics. However, even within the SSRI class, differences in efficacy or tolerability exist between the individual drugs. Among the three most widely prescribed SSRIs are paroxetine, sertraline, and escitalopram. Escitalopram is commonly referred to as an SSRI, but also has well-documented allosteric properties, and thus can be further classed as an allosteric serotonin reuptake inhibitor. All three antidepressants are efficacious compared with placebo, but there is evidence that escitalopram is more effective than a range of other antidepressants. There are no direct data to regard either paroxetine or sertraline as a superior antidepressant. Escitalopram is superior compared with paroxetine, which has a less favorable tolerability profile. Paroxetine is associated with cholinergic muscarinic antagonism and potent inhibition of CYP2D6, and sertraline has moderate drug interaction issues in comparison with escitalopram. Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escitalopram could be more efficacious, based on its interaction with orthosteric and allosteric binding sites at the serotonin transporter. © 2014 Wolters Kluwer Health | Lippincott Williams &Wilkins. Source

Leiser S.C.,Lundbeck Research United States Inc. | Dunlop J.,Pfizer | Bowlby M.R.,Merck And Co. | Devilbiss D.M.,University of Wisconsin - Madison
Biochemical Pharmacology

Electroencephalography (EEG) and related methodologies offer the promise of predicting the likelihood that novel therapies and compounds will exhibit clinical efficacy early in preclinical development. These analyses, including quantitative EEG (e.g. brain mapping) and evoked/event-related potentials (EP/ERP), can provide a physiological endpoint that may be used to facilitate drug discovery, optimize lead or candidate compound selection, as well as afford patient stratification and Go/No-Go decisions in clinical trials. Currently, the degree to which these different methodologies hold promise for translatability between preclinical models and the clinic have not been well summarized. To address this need, we review well-established and emerging EEG analytic approaches that are currently being integrated into drug discovery programs throughout preclinical development and clinical research. Furthermore, we present the use of EEG in the drug development process in the context of a number of major central nervous system disorders including Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder, and pain. Lastly, we discuss the requirements necessary to consider EEG technologies as a biomarker. Many of these analyses show considerable translatability between species and are used to predict clinical efficacy from preclinical data. Nonetheless, the next challenge faced is the selection and validation of EEG endpoints that provide a set of robust and translatable biomarkers bridging preclinical and clinical programs. © 2010 Elsevier Inc. Source

Nguyen H.,Texas A&M University | Ma G.,Texas A&M University | Ma G.,Lundbeck Research United States Inc. | Romo D.,Texas A&M University
Chemical Communications

A concise, enantioselective synthesis of the Phase I anticancer agent, (-)-salinosporamide A, is described. The brevity of the described strategy stems from a key bis-cyclization of a β-keto tertiary amide, accomplished on gram scale, which retains optical purity enabled by A1,3-strain rendering epimerization slow relative to the rate of bis-cyclization. The versatility of the strategy for derivative synthesis is demonstrated by the synthesis of (-)-homosalinosporamide A. © 2010 The Royal Society of Chemistry. Source

Wilson F.J.,Medical Imaging and Physiological Measurements Consultant | Leiser S.C.,Lundbeck Research United States Inc. | Ivarsson M.,Astrazeneca | Christensen So.R.,Lundbeck | Bastlund J.F.,Lundbeck
Drug Discovery Today

Pharmaco-electroencephalography has significant yet unrealised promise as a translatable intermediate biomarker of central pharmacodynamic activity that could help reduce Phase 2 attrition in the development of central nervous system drugs. In an effort to understand its true potential, a framework for decision-making was proposed and the utility of pharmaco-electroencephalography was assessed through several case studies. A key finding was that lack of standardisation reduces the value of data pooling and meta-analyses and renders assessment of translatability difficult, limiting utility in all but simple cases. Pre-competitive collaboration is essential both to improving understanding of translation and developing modern signal processing techniques. © 2013 Elsevier Ltd. Source

Westrich L.,Lundbeck Research United States Inc. | Sprouse J.,Lundbeck Research United States Inc.
Current Opinion in Investigational Drugs

When circadian rhythms - the daily oscillations of various physiological and behavioral events that are controlled by a central timekeeping mechanism - become desynchronized with the prevailing light:dark cycle, a maladaptative response can result. Animal data based primarily on genetic manipulations and clinical data from biomarker and gene expression studies support the notion that circadian abnormalities underlie certain psychiatric disorders. In particular, bipolar disorder has an interesting link to rhythm-related disease biology; other mood disturbances, such as major depressive disorder, seasonal affective disorder and the agitation and aggression accompanying severe dementia (sundowning), are also linked to changes in circadian rhythm function. Possibilities for pharmacological intervention derive most readily from the molecular oscillator, the cellular machinery that drives daily rhythms. © Thomson Reuters (Scientific) Ltd. Source

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