Effect of Pharmaceutical Interventions Targeting Thromboxane Receptors and Thromboxane Synthase in Cardiovascular and Renal Diseases

Sakariassen, Kjell S.; Alberts, Pēteris; Fontana, Pierre; Mann, Jessica; Bounameaux, Henri; Sorensen, Alexandra Santana

doi:10.2217/fca.09.33

Cited by 26 publications

(28 citation statements)

References 120 publications

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“…Results from probing the molecule databases implemented in SEA [39] with the 57 T. cruzi -active hits, either individually or as a pool, indicated CYP51's similarity to other P450 drug targets, including thromboxane synthase (CYP5), fatty acid ω-hydroxylases (CYP4), 17α-hydroxylase/17,20-lyase (CYP17), and aromatase (CYP19). These enzymes have been targeted by the pharmaceutical industry for cardiovascular disease [40], metabolic disorders of lipid metabolism and inflammation [41], prostate cancer [42], and estrogen receptor-positive breast cancer [43], respectively. Unexpectedly, these pharmacologic targets scored substantially higher than sterol 14α-demethylase (CYP51) itself, giving credence to the idea that molecules directed against these targets, including drugs that have entered the clinic, could be examined for potency against T. cruzi CYP51.…”

Section: Resultsmentioning

confidence: 99%

Diverse Inhibitor Chemotypes Targeting Trypanosoma cruzi CYP51

et al. 2012

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BackgroundChagas Disease, a WHO- and NIH-designated neglected tropical disease, is endemic in Latin America and an emerging infection in North America and Europe as a result of population moves. Although a major cause of morbidity and mortality due to heart failure, as well as inflicting a heavy economic burden in affected regions, Chagas Disease elicits scant notice from the pharmaceutical industry because of adverse economic incentives. The discovery and development of new routes to chemotherapy for Chagas Disease is a clear priority.Methodology/Principal FindingsThe similarity between the membrane sterol requirements of pathogenic fungi and those of the parasitic protozoon Trypanosoma cruzi, the causative agent of Chagas human cardiopathy, has led to repurposing anti-fungal azole inhibitors of sterol 14α-demethylase (CYP51) for the treatment of Chagas Disease. To diversify the therapeutic pipeline of anti-Chagasic drug candidates we exploited an approach that included directly probing the T. cruzi CYP51 active site with a library of synthetic small molecules. Target-based high-throughput screening reduced the library of ∼104,000 small molecules to 185 hits with estimated nanomolar KD values, while cross-validation against T. cruzi-infected skeletal myoblast cells yielded 57 active hits with EC50 <10 µM. Two pools of hits partially overlapped. The top hit inhibited T. cruzi with EC50 of 17 nM and was trypanocidal at 40 nM.Conclusions/SignificanceThe hits are structurally diverse, demonstrating that CYP51 is a rather permissive enzyme target for small molecules. Cheminformatic analysis of the hits suggests that CYP51 pharmacology is similar to that of other cytochromes P450 therapeutic targets, including thromboxane synthase (CYP5), fatty acid ω-hydroxylases (CYP4), 17α-hydroxylase/17,20-lyase (CYP17) and aromatase (CYP19). Surprisingly, strong similarity is suggested to glutaminyl-peptide cyclotransferase, which is unrelated to CYP51 by sequence or structure. Lead compounds developed by pharmaceutical companies against these targets could also be explored for efficacy against T. cruzi.

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Section: Resultsmentioning

confidence: 99%

Diverse Inhibitor Chemotypes Targeting Trypanosoma cruzi CYP51

et al. 2012

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“…Thromboxane A 2 (TXA 2 ) synthase can then use these prostaglandins to produce TXA 2 , a high-affinity lipid mediator that triggers potent vasoand broncho-constrictions (3,33). These effects are directly mediated by the activation of the thromboxane-prostanoid receptor (TP-receptor), a G protein-coupled receptor (27).…”

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confidence: 99%

Improved bioavailability of epoxyeicosatrienoic acids reduces TP-receptor agonist-induced tension in human bronchi

Senouvo¹,

Tabet²,

Morin³

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Epoxyeicosatrienoic acid (EET) and thromboxane A(2) are arachidonic acid derivatives. The former has initially been defined as an epithelium-derived hyperpolarizing factor displaying broncho-relaxing and anti-inflammatory properties, as recently demonstrated, whereas thromboxane A(2) induces vaso- and bronchoconstriction upon binding to thromboxane-prostanoid (TP)-receptor. EETs, however, are quickly degraded by the soluble epoxide hydrolase (sEH) into inactive diol compounds. The aim of this study was to investigate the effects of 14,15-EET on TP-receptor activation in human bronchi. Tension measurements performed on native bronchi from various species, acutely treated with increasing 14,15-EET concentrations, revealed specific and concentration-dependent relationships as well as a decrease in the tension induced by 30 nM U-46619, used as a synthetic TP-receptor agonist. Interestingly, acute treatments with 3 μM N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide, an epoxygenase inhibitor, which minimizes endogenous production of EET, resulted in an increased reactivity to U-46619. Furthermore, we demonstrated that chronic treatments with trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a sEH inhibitor, reduced human bronchi reactivity to U-46619. During our tension measurements, we also observed that human bronchi generated small-amplitude contractions; these spontaneous activities were reduced upon acute 14,15-EET treatments in the presence of t-AUCB. Altogether, these data demonstrate that endogenous and exogenous 14,15-EET could interfere with the activation of TP-receptors as well as with spontaneous oscillations in human airway smooth muscle tissues.

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“…TxA 2 is implicated in many cardiovascular, renal and respiratory diseases [21]. Much of these problems is associated with TxA 2 -induced smooth muscle contraction, which leads to vascular constriction, ischemia, pulmonary hypertension and broncho-constriction [22], [23].…”

Section: Discussionmentioning

confidence: 99%

Cyclic Nucleotide-Gated Channels Contribute to Thromboxane A2-Induced Contraction of Rat Small Mesenteric Arteries

Leung

Huang

et al. 2010

PLoS ONE

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BackgroundThromboxane A2 (TxA2)-induced smooth muscle contraction has been implicated in cardiovascular, renal and respiratory diseases. This contraction can be partly attributed to TxA2-induced Ca2+ influx, which resulted in vascular contraction via Ca2+-calmodulin-MLCK pathway. This study aims to identify the channels that mediate TxA2-induced Ca2+ influx in vascular smooth muscle cells.Methodology/Principal FindingsApplication of U-46619, a thromboxane A2 mimic, resulted in a constriction in endothelium-denuded small mesenteric artery segments. The constriction relies on the presence of extracellular Ca2+, because removal of extracellular Ca2+ abolished the constriction. This constriction was partially inhibited by an L-type Ca2+ channel inhibitor nifedipine (0.5–1 µM). The remaining component was inhibited by L-cis-diltiazem, a selective inhibitor for CNG channels, in a dose-dependent manner. Another CNG channel blocker LY83583 [6-(phenylamino)-5,8-quinolinedione] had similar effect. In the primary cultured smooth muscle cells derived from rat aorta, application of U46619 (100 nM) induced a rise in cytosolic Ca2+ ([Ca2+]i), which was inhibited by L-cis-diltiazem. Immunoblot experiments confirmed the presence of CNGA2 protein in vascular smooth muscle cells.Conclusions/SignificanceThese data suggest a functional role of CNG channels in U-46619-induced Ca2+ influx and contraction of smooth muscle cells.

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Effect of Pharmaceutical Interventions Targeting Thromboxane Receptors and Thromboxane Synthase in Cardiovascular and Renal Diseases

Cited by 26 publications

References 120 publications

Diverse Inhibitor Chemotypes Targeting Trypanosoma cruzi CYP51

Diverse Inhibitor Chemotypes Targeting Trypanosoma cruzi CYP51

Improved bioavailability of epoxyeicosatrienoic acids reduces TP-receptor agonist-induced tension in human bronchi

Cyclic Nucleotide-Gated Channels Contribute to Thromboxane A2-Induced Contraction of Rat Small Mesenteric Arteries

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