Chiral aziridine ring opening: facile synthesis of (R)-mexiletine and (R)-phenoxybenzamine hydrochloride

Viswanadh, N.; Velayudham, R.; Jambu, Subramanian; Sasikumar, M.; Muthukrishnan, M.

doi:10.1016/j.tetlet.2015.07.032

Cited by 13 publications

(3 citation statements)

References 36 publications

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“…Traditionally, the racemates were resolved into their individual enantiomers by chiral separation using supercritical fluid chromatography (SFC) on a Chiralpak AD column . In this work, enantiopure ( R )-(−)-/( S )-(+)-epichlorohydrin and ( S )-(+)-/( R )-(−)-3-chloropropane-1,2-diol were employed as starting compounds to provide enantiopure final products as reported. − …”

Section: Discussionmentioning

confidence: 99%

Synthesis and Monkey-PET Study of (R)- and (S)-¹⁸F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in Vivo Kinetics

et al. 2016

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This study describes an effective strategy to improve pharmacokinetics of Aβ imaging agents, offering a novel class of (R)- and (S)-F-labeled 2-arylbenzoheterocyclic derivatives which bear an additional chiral hydroxyl group on the side chain. These ligands displayed binding abilities toward Aβ aggregates with K values ranging from 3.2 to 195.6 nM. Chirality-related discrepancy was observed in biodistribution, and (S)-2-phenylbenzoxazole enantiomers exhibited vastly improved brain clearance with washout ratios higher than 20. Notably, (S)-[F]28 possessed high binding potency (K = 7.6 nM) and exceptional brain kinetics (9.46% ID/g at 2 min, brain/brain = 27.8) that is superior to well-established [F]AV45. The excellent pharmacokinetics and low nonspecific binding of (S)-[F]28 were testified by dynamic PET/CT scans in monkey brains. In addition, (S)-[F]28 clearly labeled Aβ plaques both in vitro and ex vivo. These results might qualify (S)-[F]28 to detect Aβ plaques with high signal-to-noise ratio.

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Section: Discussionmentioning

confidence: 99%

Synthesis and Monkey-PET Study of (R)- and (S)-¹⁸F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in Vivo Kinetics

et al. 2016

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“…Specifically, the chiral alcohol 1-(2,6dimethylphenoxy)propan-2-ol, when submitted to other reactions with exchange of the hydroxyl group by an amino group, leads to the formation of enantiomerically pure drug (R)-Mexiletine[(2R)-1-(2,6-dimethylphenoxy)propan-2-amine]. Mexiletine in its racemic form is an antiarrhythmic agent, but in enantiomerically (R)enriched form is a compound able to block the sodium channels and has its activity enhanced [19].…”

Section: Introductionmentioning

confidence: 99%

Design of a lipase-nano particle biocatalysts and its use in the kinetic resolution of medicament precursors

Bezerra

Neto

Galvão

et al. 2017

Biochemical Engineering Journal

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“…Spectrometric and spectroscopic data were in agreement with those reported in the literature. [55,56] (…”

Section: Compound Characterizationmentioning

confidence: 99%

hERG stereoselective modulation by mexiletine‐derived ureas: Molecular docking study, synthesis, and biological evaluation

Milani

Budriesi

Tavazzani

et al. 2023

Archiv der Pharmazie

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Long QT syndrome (LQTS) is a disorder of cardiac electrophysiology resulting in life‐threatening arrhythmias; nowadays, only a few drugs are available for the management of LQTS. Focusing our attention on LQT2, one of the most common subtypes of LQTS caused by mutations in the human ether‐à‐go‐go‐related gene (hERG), in the present work, the stereoselectivity of the recently discovered mexiletine‐derived urea 8 was investigated on the hERG potassium channel. According to preliminary in silico predictions, in vitro studies revealed a stereoselective behavior, with the meso form showing the greatest hERG opening activity. In addition, functional studies on guinea pig isolated left atria, aorta, and ileum demonstrated that 8 does not present any cardiac or intestinal liability in our ex vivo studies. Due to its overall profile, (R,S)‐8 paves the way for the design and development of a new series of compounds potentially useful in the treatment of both congenital and drug‐induced forms of LQTS.

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Chiral aziridine ring opening: facile synthesis of (R)-mexiletine and (R)-phenoxybenzamine hydrochloride

Cited by 13 publications

References 36 publications

Synthesis and Monkey-PET Study of (R)- and (S)-¹⁸F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in Vivo Kinetics

Synthesis and Monkey-PET Study of (R)- and (S)-¹⁸F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in Vivo Kinetics

Design of a lipase-nano particle biocatalysts and its use in the kinetic resolution of medicament precursors

hERG stereoselective modulation by mexiletine‐derived ureas: Molecular docking study, synthesis, and biological evaluation

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Chiral aziridine ring opening: facile synthesis of (R)-mexiletine and (R)-phenoxybenzamine hydrochloride

Cited by 13 publications

References 36 publications

Synthesis and Monkey-PET Study of (R)- and (S)-18F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in Vivo Kinetics

Synthesis and Monkey-PET Study of (R)- and (S)-18F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in Vivo Kinetics

Design of a lipase-nano particle biocatalysts and its use in the kinetic resolution of medicament precursors

hERG stereoselective modulation by mexiletine‐derived ureas: Molecular docking study, synthesis, and biological evaluation

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Synthesis and Monkey-PET Study of (R)- and (S)-¹⁸F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in Vivo Kinetics

Synthesis and Monkey-PET Study of (R)- and (S)-¹⁸F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in Vivo Kinetics