Pyridyl-phenyl ether monoamine reuptake inhibitors: Impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity

Whitlock, Gavin A.; Fish, Paul V.; Fray, M. Jonathan; Stobie, Alan; Wakenhut, Florian

doi:10.1016/j.bmcl.2008.03.082

Cited by 28 publications

(20 citation statements)

References 17 publications

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“…Interestingly, ( R )‐1‐(2‐(2‐ethoxyphenyl)‐1‐phenylethyl)piperazine (PF‐526014, Figure A) and closely related analogs were shown to behave as dual serotonin and noradrenaline reuptake inhibitors with good selectivity over dopamine inhibition. The lipophilic nature associated with some particular analogs also demonstrated a range of off‐target effects associated with other biological targets . Whether these particular analogs are available as ‘research chemicals’, however, is not known.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Test purchase, synthesis, and characterization of 2‐methoxydiphenidine (MXP) and differentiation from its meta‐ and para‐substituted isomers

McLaughlin

Morris

Kavanagh

et al. 2015

Drug Testing and Analysis

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The structurally diverse nature of the 1,2‐diphenylethylamine template provides access to a range of substances for drug discovery work but some have attracted attention as ‘research chemicals’. The most recent examples include diphenidine, i.e. 1‐(1,2‐diphenylethyl)piperidine and 2‐methoxydiphenidine, i.e. 1‐[1‐(2‐methoxyphenyl)‐2‐phenylethyl]piperidine (MXP, methoxyphenidine, 2‐MXP) that have been associated with uncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist activity. Analytical challenges encountered during chemical analysis include the presence of positional isomers. Three powdered samples suspected to contain 2‐MXP were obtained from three Internet retailers in the United Kingdom and subjected to analytical characterization by gas chromatography (GC) and high performance liquid chromatography (HPLC) coupled to various forms of mass spectrometry (MS). Nuclear magnetic resonance spectroscopy, infrared spectroscopy and thin layer chromatography were also employed. This was supported by the synthesis of all three isomers (2‐, 3‐ and 4‐MXP) by two different synthetic routes. The analytical data obtained for the three purchased samples were consistent with the synthesized 2‐MXP standard and the differentiation between the isomers was possible. Distinct stability differences were observed for all three isomers during in‐source collision‐induced dissociation of the protonated molecule when employing detection under HPLC selected‐ion monitoring detection, which added to the ability to differentiate between them. Furthermore, the analysis of a 2‐MXP tablet by matrix assisted inlet ionization Orbitrap mass spectrometry confirmed that it was possible to detect the protonated molecule of 2‐MXP directly from the tablet surface following addition of 3‐nitrobenzonitrile as the matrix. Copyright © 2015 John Wiley & Sons, Ltd.

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Section: Introductionmentioning

confidence: 99%

“…The lipophilic nature associated with some particular analogs also demonstrated a range of off-target effects associated with other biological targets. [12][13][14][15][16] Whether these particular analogs are available as 'research chemicals', however, is not known.…”

Section: Introductionmentioning

confidence: 99%

Test purchase, synthesis, and characterization of 2‐methoxydiphenidine (MXP) and differentiation from its meta‐ and para‐substituted isomers

McLaughlin

Morris

Kavanagh

et al. 2015

Drug Testing and Analysis

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“…[8] Several studies found that promiscuity increases with lipophilicity. [8,[11][12][13] Bases are more prone to promiscuity than uncharged compounds and acids. [12] These studies were performed with different datasets, such as the BioPrint dataset, [12,14] Pfizer HTS and project data, [11] or Novartis safety pharmacology profiling (SPP) data.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Promiscuity: Dependence on Compound Properties and Target Specificity in a Set of Recent Roche Compounds

et al. 2009

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The term "pharmacological promiscuity" describes a compound's pharmacological activity at multiple targets. Pharmacological promiscuity is undesired in typical drug discovery projects, which focus on the "one drug-one target" paradigm. Off-target activity can lead to adverse drug reactions, or can obscure pharmacodynamic effects in animal models. Therefore, advanced lead compounds, pharmacological tool compounds, and drug candidates are usually screened against panels of safety-relevant targets to detect unwanted pharmacological activities. To identify determinants of pharmacological promiscuity, we compared the panel screening outcomes of 213 recent Roche compounds with their molecular properties. Pronounced promiscuity was not observed below a threshold Clog P value of 2. For basic compounds, the propensity for weak off-target activity was found to increase with calculated basicities, whereas the potential for strong off-target activity depends more qualitatively on the presence of a positive charge at physiological pH. Compounds originating from projects with an aminergic receptor or transporter as a therapeutic target are particularly prone to promiscuity; the promiscuity of such compounds is mainly caused by their activity at other aminergic targets in the screening panel.

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“…Such pharmacological promiscuity is possibly required for certain central indications, such as psychosis, depression, Alzheimers disease [34][35][36][37] and possibly also for cancer [38], but it is certainly also the source of the many known side effects of such drugs [39,40]. Several authors use the term polypharmacology for this phenomenon [41][42][43], but this term was introduced for the broad pharmacology obtained by combination therapies, irrespective of the number of targets hit [44,45]. Due to the higher risk of side effects occurring with pharmacologically promiscuous compounds, it makes sense to promote compounds during the research phase which are inherently selective.…”

Section: Pharmacological Promiscuity and Its Clinical Interpretationmentioning

confidence: 99%

In Vitro Safety Pharmacology Profiling: An Important Tool to Decrease Attrition

Hamon

Whitebread²

2009

Hit and Lead Profiling

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Safety pharmacology is a term which started to be used in the early 1990s, specifically for the in vivo pharmacology assays designed to detect adverse effects of drugs in preclinical development. At that time, in vitro pharmacology was included under the term general pharmacology, which encompassed all in vivo and in vitro assays designed to characterize the pharmacology of a clinical candidate, including both desired and undesired effects [1][2][3]. The concept of using general pharmacology to profile drugs for safety or pharmacological toxicity was already well understood [4]. In 2001, some guidance for the industry was published (ICH S7A) defining safety pharmacology studies as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure within the therapeutic range and above [5]. While the S7A guidance largely deals with in vivo safety pharmacology studies, it states that in vitro studies on receptors, enzymes, transporters and ion channels can also be used as test systems and data from ligand binding and enzyme assays, suggesting that a potential for adverse effects should be taken into consideration when designing safety pharmacology studies. We classify these studies as in vitro safety pharmacology and the routine testing of compounds during early drug discovery we call in vitro safety pharmacology profiling [6].In vitro safety pharmacology assays have been around for more than 35 years -ever since the first in vitro pharmacology assays were developed to measure binding or activity at a specific protein. Initially of course, they were used to discover new medicines acting through such targets. However, it quickly became clear, especially for those working in the cardiovascular and neuroscience fields, that many of these targets were also responsible for unwanted side effects seen in animal experiments and humans, and testing (profiling) of new drug candidates against a number of these safety-related targets (also called antitargets [7]) was performed.Hit and Lead Profiling. Edited by Bernard Faller and Laszlo Urban

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Pyridyl-phenyl ether monoamine reuptake inhibitors: Impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity

Cited by 28 publications

References 17 publications

Test purchase, synthesis, and characterization of 2‐methoxydiphenidine (MXP) and differentiation from its meta‐ and para‐substituted isomers

Test purchase, synthesis, and characterization of 2‐methoxydiphenidine (MXP) and differentiation from its meta‐ and para‐substituted isomers

Pharmacological Promiscuity: Dependence on Compound Properties and Target Specificity in a Set of Recent Roche Compounds

In Vitro Safety Pharmacology Profiling: An Important Tool to Decrease Attrition

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