Rapid access to enantiopure bupropion and its major metabolite by stereospecific nucleophilic substitution on an α-ketotriflate

Fang, Q. Kevin; Han, Zhengxu S.; Grover, Paul; Kessler, Donald W.; Senanayake, Chris H.; Wald, Stephen A.

doi:10.1016/s0957-4166(00)00349-9

Cited by 87 publications

(62 citation statements)

References 8 publications

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“…1,5 In vitro studies indicate that bupropion is metabolized to hydroxybupropion primarily by cytochrome P450 2B6 (CYP2B6). 8,9 Two enantiomers, (2R,3R)-and (2S,3S)-hydroxybupropion have been identified, 3 with (2R,3R)-hydroxybupropion being predominant in human plasma. 7 Racemisation of the enantiomers of hydroxybupropion has been reported at a rate of 2% in 24 h (pH 7.4 phosphate buffer at 258C).…”

Section: Bupropion (Amfebutamone) (Rac)-2-tert-butylamino-3mentioning

confidence: 99%

“…1 It has one chiral center, which is used clinically as a racemic mixture 2 and its enantiomers have been shown to undergo rapid racemisation in solution. 3 Bupropion is metabolized to three active metabolites: hydroxybupropion, erythrohydrobupropion, and threohydrobupropion ( Fig. 1), which are further metabolized to inactive metabolites and subsequently excreted in urine.…”

Section: Bupropion (Amfebutamone) (Rac)-2-tert-butylamino-3mentioning

confidence: 99%

“…7 Racemisation of the enantiomers of hydroxybupropion has been reported at a rate of 2% in 24 h (pH 7.4 phosphate buffer at 258C). 3 A number of in vitro and in vivo studies have investigated the pharmacological actions and the pharmacokinetics of (rac)-bupropion and its active metabolite (rac)-hydroxybupropion using achiral assays. 5,[10][11][12] Recent studies suggest that the therapeutic effects of bupropion are because of enhancement of noradrenergic and dopaminergic signals, 13,14 as well as noncompetitive antagonism at various nicotinic receptors.…”

Section: Bupropion (Amfebutamone) (Rac)-2-tert-butylamino-3mentioning

confidence: 99%

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Stereoselective analysis of hydroxybupropion and application to drug interaction studies

Loboz

Gross

et al. 2006

Chirality

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A sensitive and stereoselective assay has been developed for the quantitation of the enantiomers of hydroxybupropion, an active metabolite of bupropion, in human plasma. The assay used liquid-liquid extraction and a Cyclobond I 2000 HPLC column with a mobile phase containing 3% acetonitrile, 0.5% triethylamine, and 20 mM ammonium acetate (pH 3.8). The technique was linear over the concentration range of 12.5-500 ng/ml for (2R,3R)- and (2S,3S)-hydroxybupropion. The method was reproducible as both interday and intraday variabilities were less than 10% for both hydroxybupropion enantiomers. Overall extraction recovery of hydroxybupropion enantiomers and the internal standard phenacetin from plasma was greater than 80% and reproducible over the concentration range of 12.5-500 ng/ml for each enantiomer. The limit of quantification (LOQ) of hydroxybupropion enantiomers was 12.5 ng/ml. The stereoselective pharmacokinetics of both (2R,3R)- and (2S,3S)-hydroxybupropion in healthy male subjects (n = 16) were investigated after a single dose of (rac)-bupropion either alone or during rifampicin administration. (2R,3R)-Hydroxybupropion was the predominant enantiomer present in plasma. A stereoselective effect of rifampicin on hydroxybupropion concentrations was observed, with rifampicin influencing the pharmacokinetics of each hydroxybupropion enantiomer in a different manner. The ratio of (2R,3R)-hydroxybupropion (AUC(0-24)) to (2S,3S)-hydroxybupropion (AUC(0-24)) increased from 4.9 +/- 1.6 to 8.3 +/- 1.9 during rifampicin administration (P < 0.001). A time-dependent change in the hydroxybupropion enantiomeric ratio was observed after (rac)-bupropion administration both before and during rifampicin coadministration, with an increase in the relative proportion of (2S,3S)-hydroxybupropion over the 24 h postdose period.

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Section: Bupropion (Amfebutamone) (Rac)-2-tert-butylamino-3mentioning

confidence: 99%

Section: Bupropion (Amfebutamone) (Rac)-2-tert-butylamino-3mentioning

confidence: 99%

Section: Bupropion (Amfebutamone) (Rac)-2-tert-butylamino-3mentioning

confidence: 99%

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Stereoselective analysis of hydroxybupropion and application to drug interaction studies

Loboz

Gross

et al. 2006

Chirality

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“…Bupropion HCl was purchased from Sigma/RBI (Natick, MA). (ϩ)-(2S,3S)-and (Ϫ)-(2S,3R)-hydroxybupropion tartrates were synthesized using methods reported previously (Fang et al, 2000). All drugs were dissolved in physiological saline (0.9% sodium chloride) and given in a total volume of 1 ml per 100 g body weight for subcutaneous injections.…”

Section: In Vivo Studiesmentioning

confidence: 99%

Enantioselective Effects of Hydroxy Metabolites of Bupropion on Behavior and on Function of Monoamine Transporters and Nicotinic Receptors

Carroll²,

et al. 2004

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Bupropion is an atypical antidepressant that also has usefulness as a smoking-cessation aid. Because hydroxybupropion, a major metabolite of bupropion, is believed to contribute to its antidepressant activity, this metabolite may also contribute to the smoking-cessation properties of bupropion. This study investigated the effects of hydrobupropion enantiomers on monoamine transporters and nicotinic acetylcholine receptor (nAChR) subtypes. Racemic bupropion and hydroxybupropion inhibit [3 H]norepinephrine (NE) uptake with similar potency (IC 50 values of 1.9 and 1.7 M, respectively), but most of the latter activity resides in the (2S,3S)-hydroxy isomer (IC 50 ϭ 520 nM) rather than (2S,3R)-hydroxybupropion (IC 50 Ͼ 10,000 nM). Similar results were found with [ 3 H]dopamine (DA) uptake. The effects of bupropion and enantiomers of hydroxybupropion on human nAChR subtypes indicate that the (2S,3S) isomer is more potent than the (2S,3R) isomer or racemic bupropion as an antagonist of ␣ 4 ␤ 2 (functional IC 50 ϭ 3.3 M). In addition, (2S,3S)-hyroxybupropion and bupropion were considerably more potent than (2R, Ϫ3R)-hydroxybupropion in a mouse depression model (forced swimming test) and in antagonism of acute nicotine effects in mice. Together, our results suggest that clinical and behavioral effects of bupropion arise from actions at nAChR as well as DA and NE transporters. Furthermore, our data suggest that the (2S,3S)-hydroxybupropion isomer may be a better drug candidate for smoking cessation than bupropion because of its higher potency at the relevant targets.Tobacco use is the leading cause of premature death in the United States. The vast majority of smokers (70%) report a desire to quit smoking, but poor smoking-cessation results indicate a need to explore innovative approaches to treating nicotine addiction. In addition to nicotine-replacement therapy, the atypical antidepressant bupropion is now recognized as an effective aid to smoking cessation. The efficacy of bupropion in the treatment of nicotine dependence was believed to involve the modulation of dopaminergic (dopamine, DA) and noradrenergic (norepinephrine, NE) systems. Indeed, bupropion is a relatively weak DA-reuptake inhibitor and inhibits the firing of locus coeruleus NE neurons at high concentrations (Cooper et al., 1994). Its inhibition of transporter function is associated with increases in extracellular DA and NE concentrations, which may substitute for nicotine-evoked neurotransmitter release during smoking, mimicking nicotine reinforcement and alleviating withdrawal symptoms stemming from the absence of nicotine. No other neuronal sites were believed to play a role in bupropion's because of its lack of binding affinity for almost all of the major classes of neuronal receptors (Ascher et al., 1995).However, findings from our laboratories that bupropion acted as a relatively potent, noncompetitive nAChR antagonist suggested that actions of bupropion at nAChR were of possible relevance for smoking cessation, especially given the ABBREVIAT...

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“…(R)-1-(3-Chloro-phenyl)-2-hydroxy-propan-1-one (3a) is produced from 1a and 2a and acts as a precursor in the synthesis of bupropion (Fang et al, 2000), which is the agent used in Zyban 1 as an aid to smoking cessation treatment (see Fig. 1).…”

mentioning

confidence: 99%

The production of (R)‐2‐hydroxy‐1‐phenyl‐propan‐1‐one derivatives by benzaldehyde lyase from Pseudomonas fluorescens in a continuously operated membrane reactor

Hildebrand

Kühl

Pohl

et al. 2006

Biotech & Bioengineering

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Benzaldehyde lyase (BAL; E.C. 4.1.2.38) from Pseudomonas fluorescens Biovar I catalyzes the reversible formation of benzoins from aromatic aldehydes, and, moreover, the coupling of aromatic with aliphatic aldehydes yielding derivatives of (R)-2-hydroxy-1-phenyl- propan-1-one (R)-HPPs), which are important chiral building blocks. In this paper, we report on the development of a reactor system that allows the selective production of substituted (R)-HPP-derivatives. The reaction systems yielding (R)-1-(3-chloro-phenyl)-2-hydroxy- propan-1-one, (R)-2-hydroxy-3-methoxy-1-(4-methoxy-phenyl)-propan-1-one, and (R)-2-hydroxy-3,3-dimethoxy-1-phenyl-propan-1-one were investigated. A kinetic model optimized by batch experiments was developed, for the description of both batch and continuously operated reactors. This model was used to describe the HPP production in a continuously operated enzyme membrane reactor. The reactor type used combines the advantages of high conversion and excellent selectivity with high space-time yields and total turnover numbers of up to ttn=43,000. Products were obtained in high yield on a gram scale.

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Rapid access to enantiopure bupropion and its major metabolite by stereospecific nucleophilic substitution on an α-ketotriflate

Cited by 87 publications

References 8 publications

Stereoselective analysis of hydroxybupropion and application to drug interaction studies

Stereoselective analysis of hydroxybupropion and application to drug interaction studies

Enantioselective Effects of Hydroxy Metabolites of Bupropion on Behavior and on Function of Monoamine Transporters and Nicotinic Receptors

The production of (R)‐2‐hydroxy‐1‐phenyl‐propan‐1‐one derivatives by benzaldehyde lyase from Pseudomonas fluorescens in a continuously operated membrane reactor

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