The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

Bui, Peter; Quesada, Arnulfo; Handforth, Adrian; Hankinson, Oliver

doi:10.1124/dmd.107.020115

Cited by 27 publications

(21 citation statements)

References 33 publications

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“…In addition, the observed k inact /K i ratio of 2143 ml ⅐ min Ϫ1 ⅐ mol Ϫ1 under the current conditions suggests that CYP3A4 inactivation by mibefradil is approximately 12-fold more potent than reported previously, which places the compound among the most potent P450 inactivators observed to date (Obach et al, 2007). Bui et al (2008) investigated a hydrolysis-resistant analog of mibefradil [(1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl cyclopropanecarboxylate dihydrochloride (NNC55-0396)], in which the methoxyacetyl side chain of mibefradil was replaced with a cyclopropylacetyl moiety and observed decreased time-dependent inhibition of CYP3A4. The previous study also demonstrated the inhibitory potential of Ro 40-5966 toward CYP3A4, although not with respect to time-dependent inhibition.…”

Section: Discussionmentioning

confidence: 52%

“…The synthesis of the des-methoxyacetyl metabolite of mibefradil was performed as described previously (Bui et al, 2008;Wu et al, 2008). In brief, 100 mg of mibefradil was dissolved in ethanol-1 N NaOH (50:50) and stirred at room temperature for 4 h. Complete hydrolysis of the ester bond was confirmed by thin-layer chromatography and LC-UV/MS comparison to a mibefradil standard.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism-Based Inactivation of Cytochrome P450 3A4 by Mibefradil through Heme Destruction

Foti

Rock²,

Pearson³

et al. 2011

Drug Metab Dispos

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Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Mibefradil through Heme Destruction

Foti

Rock²,

Pearson³

et al. 2011

Drug Metab Dispos

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“…With higher concentrations, Ni 2+ and mibefradil wiped out both spiking and burst firings (Figure 4, A and B). We also tested NNC 55-0396, which was reported as a very specific T-channel inhibitor (37)(38)(39). NNC 55-0396 inhibited LVA Ca 2+ currents, turned burst into spiking discharges at low concentration, and wiped out both spiking and burst discharges at high concentration in STN neurons in vitro, all of which were very similar to the effects of Ni 2+ and mibefradil ( Figure 4C).…”

Section: Figurementioning

confidence: 82%

Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease

Tai¹,

Yang²,

Pan³

et al. 2011

J. Clin. Invest.

108

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An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T-type Ca 2+ channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type Ca 2+ channels reduces motor deficits in a rat model of PD. Ni 2+ , mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type Ca 2+ currents in acutely dissociated STN neurons, but not Cd 2+ and nifedipine, which preferentially inhibited L-type or the other non-T-type Ca 2+ currents, effectively diminished burst activity in STN slices. Topical administration of inhibitors of T-type Ca 2+ channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. Cd 2+ and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type Ca 2+ channels. We therefore conclude that modulation of subthalamic T-type Ca 2+ currents and consequent burst discharges may provide new strategies for the treatment of PD.

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“…3, A and B) suggest that these kinetic schemes will result in log-linear PRA plots. However, there are many examples in the literature of curved PRA plots (He et al, 1998;Voorman et al, 1998;Kanamitsu et al, 2000;Yamano et al, 2001;Heydari et al, 2004;Obach et al, 2007;Bui et al, 2008;Foti et al, 2011). Both quasi-irreversible and partial inactivation kinetics result in concave upward plots (Figs.…”

mentioning

confidence: 99%

A Numerical Method for Analysis of In Vitro Time-Dependent Inhibition Data. Part 1. Theoretical Considerations

Nagar¹,

Jones²,

Korzekwa³

2014

Drug Metab Dispos

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Inhibition of cytochromes P450 by time-dependent inhibitors (TDI) is a major cause of clinical drug-drug interactions. It is often difficult to predict in vivo drug interactions based on in vitro TDI data. In part 1 of these manuscripts, we describe a numerical method that can directly estimate TDI parameters for a number of kinetic schemes. Datasets were simulated for Michaelis-Menten (MM) and several atypical kinetic schemes. Ordinary differential equations were solved directly to parameterize kinetic constants. For MM kinetics, much better estimates of K I can be obtained with the numerical method, and even IC 50 shift data can provide meaningful estimates of TDI kinetic parameters. The standard replot method can be modified to fit non-MM data, but normal experimental error precludes this approach. Non-MM kinetic schemes can be easily incorporated into the numerical method, and the numerical method consistently predicts the correct model at errors of 10% or less. Quasi-irreversible inactivation and partial inactivation can be modeled easily with the numerical method. The utility of the numerical method for the analyses of experimental TDI data is provided in our companion manuscript in this issue of Drug Metabolism and Disposition (Korzekwa et al., 2014b).

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The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

Abstract: ABSTRACT:A novel mibefradil derivative, NNC55-0396, designed to be hydrolysis-resistant, was shown to be a selective than its parent compound, mibefradil, which was withdrawn from the market because of strong inhibition of CYP3A4.

Cited by 27 publications

References 33 publications

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Mibefradil through Heme Destruction

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Mibefradil through Heme Destruction

Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease

A Numerical Method for Analysis of In Vitro Time-Dependent Inhibition Data. Part 1. Theoretical Considerations

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