Optimization of 2-piperidin-4-yl-acetamides as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Designing out hERG inhibition

Berglund, Susanne; Egner, Bryan J.; Gradén, Henrik; Gradén, Joakim; Morgan, David; Inghardt, Tord; Giordanetto, Fabrizio

doi:10.1016/j.bmcl.2009.05.067

Cited by 8 publications

(6 citation statements)

References 19 publications

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“…In pair 3, introduction of the second chlorine on the ring reduces hERG affinity by 0.43 log units. 77 The authors of the original publication argue that the second chlorine increases the acidity of the aromatic hydroxy group and thereby reduces the overall lipophilicity of the compound. This inductive effect of the chlorine is to be expected, but it will only make a difference if there is another group whose acidity can be modified.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Matched Molecular Pair Analysis: Significance and the Impact of Experimental Uncertainty

Krämer

Fuchs

Whitebread³

et al. 2014

J. Med. Chem.

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Matched molecular pair analysis (MMPA) has become a major tool for analyzing large chemistry data sets for promising chemical transformations. However, the dependence of MMPA predictions on data constraints such as the number of pairs involved, experimental uncertainty, source of the experiments, and variability of the true physical effect has not yet been described. In this contribution the statistical basics for judging MMPA are analyzed. We illustrate the connection between overall MMPA statistics and individual pairs with a detailed comparison of average CHEMBL hERG MMPA results versus pairs with extreme transformation effects. Comparing the CHEMBL results to Novartis data, we find that significant transformation effects agree very well if the experimental uncertainty is considered. This indicates that caution must be exercised for predictions from insignificant MMPAs, yet highlights the robustness of statistically validated MMPA and shows that MMPA on public databases can yield results that are very useful for medicinal chemistry.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Matched Molecular Pair Analysis: Significance and the Impact of Experimental Uncertainty

Krämer

Fuchs

Whitebread³

et al. 2014

J. Med. Chem.

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“…Substitution of the piperidine ring of GZ-793A for a piperazine ring may reduce interactions with the hERG channel, while maintaining activity at VMAT2. Alternatively, increasing the polarity of the molecule through halogen substitution of the lipophilic phenyl rings (Meyers et al, 2007) or replacing the phenyl rings with pyridine rings (Berglund et al, 2009) also may reduce interactions with hERG channel. Of note, lobelane analogs which exhibit a number of these structural modifications potently inhibit VMAT2 function (Nickell et al, 2011(Nickell et al, , 2014(Nickell et al, , 2016, and such alterations may enhance hydrophilicity.…”

Section: Discussionmentioning

confidence: 99%

GZ-793A inhibits the neurochemical effects of methamphetamine via a selective interaction with the vesicular monoamine transporter-2

Nickell

Siripurapu

Horton

et al. 2017

European Journal of Pharmacology

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Lobeline and lobelane inhibit the behavioral and neurochemical effects of methamphetamine via an interaction with the vesicular monoamine transporter-2 (VMAT2). However, lobeline has high affinity for nicotinic receptors, and tolerance develops to the behavioral effects of lobelane. A water-soluble analog of lobelane, R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), also interacts selectively with VMAT2 to inhibit the effects of methamphetamine, but does not produce behavioral tolerance. The current study further evaluated the mechanism underlying the GZ-793A-mediated inhibition of the neurochemical effects of methamphetamine. In contrast to lobeline, GZ-793A does not interact with the agonist recognition site on α4β2 and α7 nicotinic receptors. GZ-793A (0.3-100µM) inhibited methamphetamine (5µM)-evoked fractional dopamine release from rat striatal slices, and did not evoke dopamine release in the absence of methamphetamine. Furthermore, GZ-793A (1-100µM) inhibited neither nicotine (30µM)-evoked nor electrical field-stimulation-evoked (100Hz/1min) fractional dopamine release. Unfortunately, GZ-793A inhibited [H]dofetilide binding to human-ether-a-go-go related gene channels expressed on human embryonic kidney cells, and further, prolonged action potentials in rabbit cardiac Purkinje fibers, suggesting the potential for GZ-793A to induce ventricular arrhythmias. Thus, GZ-793A selectively inhibits the neurochemical effects of methamphetamine and lacks nicotinic receptor interactions; however, development as a pharmacotherapy for methamphetamine use disorders will not be pursued due to its potential cardiac liabilities.

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“…The structure and the activities of the data set were obtained from the published reports of Berglund, et al and are provided in Table 1 [6]. The structure and the activities of the data set were obtained from the published reports of Berglund, et al and are provided in Table 1 [6].…”

Section: Methodsmentioning

confidence: 99%

“…A series of structurally diverse 2-piperidin-4-ylacetamide derivatives was reported with the melaninconcentrating hormone receptor-1 (MCH R1) antagonistic and the hERG blocking activities [6]. The MCH R1 antagonists have recently attracted widespread attention as a potentially viable treatment for obesity.…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis of 2-Piperidin-4-yl-Actamide Derivatives for hERG Blocking and MCH R1 Antagonistic Activities

Moorthy

Ramos²,

Fernandes³

2012

CDDT

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In the present investigation, a computational based structural analysis was performed on a series of 2-piperidin- 4-yl-acetamide derivatives to investigate the physicochemical features of the molecules responsible for the hERG blocking and melanin concentrating hormone receptor-1 (MCH R1) antagonistic activities. The QSAR models derived from MLR analysis were validated by various validation methods and they provided significant statistical results such as Q(2), F, t(test), R, predicated residual error values, etc. These significant models were constructed with different type of physicochemical descriptors which showed that the hydrophobic properties on the vdW surface of the molecules are favorable for both the activities (MCH R1 antagonistic and hERG blocking activities) and the presence of polar/electronegative groups in the molecules is detrimental for those activities. The presence of flexible aromatic rings in the molecules has favorable hERG blocking activity. The MCH R1 antagonistic activity also depends upon the vdW volume, shape and flexibility of the molecules. In addition, the presented results will guide for the optimized design of novel bioactive molecules with less/free of hERG blocking activities to avoid unwanted potential cardiotoxic side effects related with the use of these possible antiarrhythmic and anti-obesity agents in humans.

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Optimization of 2-piperidin-4-yl-acetamides as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Designing out hERG inhibition

Cited by 8 publications

References 19 publications

Matched Molecular Pair Analysis: Significance and the Impact of Experimental Uncertainty

Matched Molecular Pair Analysis: Significance and the Impact of Experimental Uncertainty

GZ-793A inhibits the neurochemical effects of methamphetamine via a selective interaction with the vesicular monoamine transporter-2

Structural Analysis of 2-Piperidin-4-yl-Actamide Derivatives for hERG Blocking and MCH R1 Antagonistic Activities

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