The discovery and development of selective 3-fluoro-4-aryloxyallylamine inhibitors of the amine oxidase activity of semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1)

Foot, Jonathan S.; Deodhar, Mandar; Turner, Catherine; Yin, Ping; Dam, Ellen M. van; Silva, Diego G.; Olivieri, Aldo; Holt, Andrew; McDonald, Ian A.

doi:10.1016/j.bmcl.2012.04.111

Cited by 29 publications

(29 citation statements)

References 20 publications

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“…The binding mode is also different from all recent computational studies, where docking and QSAR models of potential VAP-1 inhibitors have been published 19, 20, 30, 37–39 . Unlike 2HP, which binds covalently to TPQ 14 , the molecules 6 , 7 , and 13 bind non-covalently in the channel leading to the active site.…”

Section: Resultsmentioning

confidence: 59%

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

et al. 2013

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Vascular adhesion protein-1 (VAP-1) is a primary amine oxidase and a drug target for inflammatory and vascular diseases. Despite extensive attempts to develop potent, specific and reversible inhibitors of its enzyme activity, the task has proven challenging. Here we report the synthesis, inhibitory activity and molecular binding mode of novel pyridazinone inhibitors, which show specificity for VAP-1 over monoamine and diamine oxidases. The crystal structures of three inhibitor-VAP-1 complexes show that these compounds bind reversibly into a unique binding site in the active site channel. Though they are good inhibitors of human VAP-1, they do not inhibit rodent VAP-1 well. To investigate this further, we used homology modeling and structural comparison to identify amino acid differences, which explain the species-specific binding properties. Our results prove the potency and specificity of these new inhibitors and the detailed characterization of their binding mode is of importance for further development of VAP-1 inhibitors.

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Section: Resultsmentioning

confidence: 59%

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

et al. 2013

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“…Whilst mechanism-based amine oxidase inhibitors have been reported to potentially serve as substrates for some amine oxidases [15], there was no significant (> 20%) increase of AMPLEX Red signal over baseline for high concentrations (> 30 μM) of PXS-S1A for LOXL2 or MAO-B, although > 20% increases occurred for SSAO and DAO. In contrast to this, PXS-S2A did not show any significant activity against any enzyme tested even at high concentrations (LOXL2, DAO, MAO-B, SSAO).…”

Section: Resultsmentioning

confidence: 99%

Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer

et al. 2017

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Lysyl Oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases is known to be important in normal tissue development and homeostasis, as well as the onset and progression of solid tumors. Here we tested the anti-tumor properties of two generations of novel small molecule LOXL2 inhibitor in the MDA-MB-231 human model of breast cancer. We confirmed a functional role for LOXL2 activity in the progression of primary breast cancer. Inhibition of LOXL2 activity inhibited the growth of primary tumors and reduced primary tumor angiogenesis. Dual inhibition of LOXL2 and LOX showed a greater effect and also led to a lower overall metastatic burden in the lung and liver. Our data provides the first evidence to support a role for LOXL2 specific small molecule inhibitors as a potential therapy in breast cancer.

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“…PXS-4681A was found to be an inhibitor of SSAO/VAP-1 in human, rat, mouse, rabbit, and dog species with an IC 50 of ,10 nM in all cases (Table 1). This pan-species potency is a substantial improvement on the previously reported allylamine inhibitors (O'Rourke et al, 2008;Foot et al, 2012). Selectivity over the closely related DAO and LOX was shown to be excellent, at more than 250-and 4000-fold, respectively.…”

Section: Resultsmentioning

confidence: 59%

“…3A, the simultaneous application of enzyme and PXS-4681A did not cause any increase in fluorescence over background. PXS-4159A, which was previously shown to have a turnover number of approximately 10 (Foot et al, 2012), was used as a positive control. When the relative increase in fluorescence was measured after 30 minutes of incubation, no significant difference between dimethylsulfoxide background and PXS-4681A was observed, whereas PXS-4159A increased the number of counts (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Because of the considerable differences in pharmacology between species (Yu et al, 1994), it is also a challenge to design inhibitors of SSAO/VAP-1 with sufficient potencies across species (Inoue et al, 2013a,b) and thereby accurately determine their therapeutic potential and safety window. For example, PXS-4159A [(E)-4-(4-amino-2-fluorobut-2-enyloxy)-N-cyclohexylbenzamide hydrochloride; compound 3] has recently been reported as a potent, selective molecule with promising in vivo pharmacokinetic parameters that shows efficacy in a mouse model of lung inflammation when dosed orally at 100 mg/kg (Foot et al, 2012). However, despite these desirable properties, PXS-4159A was found to suffer from a narrow therapeutic window in rodents (due to poor efficacy against the rodent forms of the enzyme), limiting the study of the compound in in vivo models.…”

Section: Introductionmentioning

confidence: 99%

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PXS-4681A, a Potent and Selective Mechanism-Based Inhibitor of SSAO/VAP-1 with Anti-Inflammatory Effects In Vivo

Foot

Yow

Schilter

et al. 2013

J Pharmacol Exp Ther

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Semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1), is a member of the copperdependent amine oxidase family that is associated with various forms of inflammation and fibrosis. To investigate the therapeutic potential of SSAO/VAP-1 inhibition, potent and selective inhibitors with drug-like properties are required. PXS-4681A [(Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)benzenesulfonamide hydrochloride] is a mechanism-based inhibitor of enzyme function with a pharmacokinetic and pharmacodynamic profile that ensures complete, longlasting inhibition of the enzyme after a single low dose in vivo.PXS-4681A irreversibly inhibits the enzyme with an apparent K i of 37 nM and a k inact of 0.26 min 21 with no observed turnover in vitro. It is highly selective for SSAO/VAP-1 when profiled against related amine oxidases, ion channels, and seven-transmembrane domain receptors, and is superior to previously reported inhibitors. In mouse models of lung inflammation and localized inflammation, dosing of this molecule at 2 mg/kg attenuates neutrophil migration, tumor necrosis factor-a, and interleukin-6 levels. These results demonstrate the drug-like properties of PXS-4681A and its potential use in the treatment of inflammation.

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The discovery and development of selective 3-fluoro-4-aryloxyallylamine inhibitors of the amine oxidase activity of semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1)

Cited by 29 publications

References 20 publications

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer

PXS-4681A, a Potent and Selective Mechanism-Based Inhibitor of SSAO/VAP-1 with Anti-Inflammatory Effects In Vivo

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