Fluorinated Phenylcyclopropylamines as Inhibitors of Monoamine Oxidases

Rosén, Thomas; Yoshida, Shigeaki; Kirk, Kenneth L.; Haufe, Günter

doi:10.1002/cbic.200400053

Cited by 30 publications

(21 citation statements)

References 82 publications

(41 reference statements)

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“…These findings document that the absolute configuration of the compounds strongly influences the inhibitory potency of this enzyme. In other reports, these compounds were examined for inhibitory activity toward recombinant human liver MAO A and B. The trans isomer 16 having fluorine at the 2‐position of phenylcyclopropylamine showed higher inhibitory potency toward both MAO A and B, compared with the nonfluorinated compound 1 .…”

Section: Introductionmentioning

confidence: 99%

An Overview of Phenylcyclopropylamine Derivatives: Biochemical and Biological Significance and Recent Developments

Khan

Suzuki

Miyata

2012

Medicinal Research Reviews

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trans-2-Phencylcyclopropylamine (2-PCPA), a potent, clinically used antidepressant, affects monoamine neurotransmitter levels by inhibiting the main metabolizing enzymes, monoamine oxidases (MAOs). However, the antidepressant action of this compound was not fully explained by its effects on MAOs due to its wide variety of biological effects. 2-PCPA also affects depression-associated pathophysiological pathways, and linked with increased levels of trace amines in brain, upregulation of GABAB receptors (where GABA is gamma amino butyric acid), modulation of phospholipid metabolism, and interference with various cytochrome P450 (CYP) enzymes. Consequently, despite its adverse effects and limited clinical applicability, 2-PCPA has attracted interest as a structural scaffold for the development of mechanism-based inhibitors of various enzymes, including lysine-specific demethylase 1 (LSD1), which is a possible target for cancer chemotherapy. In the recent years, many reports have appeared in the literature based on 2-PCPA scaffold and their potential medicinal implications. This review mainly focuses on the medicinal chemistry aspects including drug design, structure-activity relationships (SAR), biological and biochemical properties, and mechanism of actions of 2-PCPA and its derivatives. Furthermore, we also highlight recent advance in this area and discuss their future applications for beneficial therapeutic effects.

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Section: Introductionmentioning

confidence: 99%

An Overview of Phenylcyclopropylamine Derivatives: Biochemical and Biological Significance and Recent Developments

Khan

Suzuki

Miyata

2012

Medicinal Research Reviews

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“…A fluoro-substituted olefin can strongly impact the property of a molecule; an example is the Z -fluoroalkene derivative of γ-aminobutyric acid (GABA) transaminase inhibitor 7 , more active than its E isomer 8 yet similarly potent and with a distinct mode of action compared to the parent non-fluorinated alkene (vigabatrin). Fluoro-olefins may be used as substrates in synthesis of fluorine-containing building blocks 9 . And still, the number of approaches for accessing alkenyl halides is limited; many entail multi-step sequences demanding prior synthesis of alkenylboron 10 , alkenylsilane 11 or an organometallic species 12,13 , followed by conversion of the C–B, C–Si or C–metal unit to a carbon–halogen bond (for a more extensive list, see the Supplementary Information).…”

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confidence: 99%

Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis

Koh

Nguyen

Zhang

et al. 2016

Nature

168

117

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Olefin metathesis has made a significant impact on modern organic chemistry, but important shortcomings remain: for example, the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the corresponding high-oxidation-state systems is very limited. In this manuscript, we show that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z-alkenyl halides. Transformations are promoted by small amounts of an in situ-generated catalyst with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents and proceed to high conversion at ambient temperature within four hours. Many alkenyl chlorides, bromides and fluorides can be obtained in up to 91 percent yield and complete Z selectivity. This method can be used to easily synthesize biologically active compounds and to perform the site- and stereoselective fluorination of other organic compounds.

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“… a p K a values were determined titrametrically in 0.1 M KNO 3 at 21 °C. b log D values were determined from the partition coefficient for 1-octanol/0.05 N NaOH + 5 Vol% DMSO at pH = 7.4. c The corresponding data were taken from the literature [6]. …”

Section: Figures and Tablesmentioning

confidence: 99%

“…Recent reports also discussed MAO inhibitors as useful agents against neurodegenerative disorders such as Parkinson’s or Alzheimer’s deceases [5]. However, 1 has little selectivity and also inhibits MAO A, B and CAOs [6]. To target the inhibition of MAO B for the treatment of above deceases, non-selective inhibitor, tranylcypromine, leads to side effects, including the well known “cheese” effect caused by inhibition of MAO A.…”

Section: Introductionmentioning

confidence: 99%