Novel and Potent Inhibitors of 5-Lipoxygenase Product Synthesis Based on the Structure of Pirinixic Acid

Werz, Oliver; Koeberle, Andreas; Hoernig, Christina; George, Sven; Popescu, Laura; Syha, Ivonne; Schubert‐Zsilavecz, Manfred; Steinhilber, Dieter

doi:10.1021/jm800588x

Cited by 25 publications

(33 citation statements)

References 21 publications

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“…The investigated pirinixic acid derivatives modulate 5-LO, mPGES1, PPARα, and PPARγ at varying potencies [3][4][5][6][7][8] and these molecules are considered as potential anti-cancer drug targets [14][15][16][17]. However, the effects of the compounds on cancer cell viability did not correlate Table 8. with their effects on 5-LO, mPGES1, PPARα, or PPARγ activity (Suppl .…”

Section: Discussionmentioning

confidence: 99%

“…In the meantime, a substantial number of pirinixic acid derivatives were synthesized that interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), cyclooxygenase (COX), microsomal prostaglandin E2 synthase-1 (mPGES1), and γ-secretase at varying potencies [3][4][5][6][7][8]. This makes pirinixic acid derivatives drug candidates for pathological states including dyslipidemia, diabetes, metabolic syndrome, hypertension, cardiovascular disease, Alzheimer's disease, and inflammation-related diseases [2,[9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

Michaelis¹,

Rothweiler²,

Wurglics³

et al. 2016

European Journal of Cancer

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Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARa, PPARg, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARa, and PPARg represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARa, or PPARg. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

Michaelis¹,

Rothweiler²,

Wurglics³

et al. 2016

European Journal of Cancer

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“…YS121 was synthesized as reported previously (Koeberle et al, 2008b;Werz et al, 2008). Pirinixic acid was purchased from Sigma-Aldrich (Deisenhofen, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…1) led to ␣-substituted pirinixic acid derivatives such as YS121 (Fig. 1), which inhibits mPGES-1 (IC 50 ϭ 3.4 M) (Koeberle et al, 2008b) and 5-lipoxygenase (IC 50 ϭ 4.1 and 6.5 M in cell-based and cell-free assays, respectively) (Werz et al, 2008) and activates peroxisome proliferator-activated receptor (PPAR)-␣ and -␥ (EC 50 ϭ 1 and 3.6 M, respectively) (Rau et al, 2008). Here, we investigated the biochemical interaction of YS121 with mPGES-1.…”

mentioning

confidence: 99%

The Molecular Pharmacology and In Vivo Activity of 2-(4-Chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a Dual Inhibitor of Microsomal Prostaglandin E₂ Synthase-1 and 5-Lipoxygenase

Koeberle

Rossi²,

Zettl³

et al. 2009

J Pharmacol Exp Ther

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The microsomal prostaglandin E 2 synthase (mPGES)-1 is one of the terminal isoenzymes of prostaglandin (PG) E 2 biosynthesis. Pharmacological inhibitors of mPGES-1 are proposed as an alternative to nonsteroidal anti-inflammatory drugs. We recently presented the design and synthesis of a series of pirinixic acid derivatives that dually inhibit mPGES-1 and 5-lipoxygenase. Here, we investigated the mechanism of mPGES-1 inhibition, the selectivity profile, and the in vivo activity of ␣-(n-hexyl)-substituted pirinixic acid [YS121; 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid)] as a lead compound. In cell-free assays, YS121 inhibited human mPGES-1 in a reversible and noncompetitive manner (IC 50 ϭ 3.4 M), and surface plasmon resonance spectroscopy studies using purified in vitro-translated human mPGES-1 indicate direct, reversible, and specific binding to mPGES-1 (K D ϭ 10 -14 M). In lipopolysaccharide-stimulated human whole blood, PGE 2 formation was concentration dependently inhibited (IC 50 ϭ 2 M), whereas concomitant generation of the cyclooxygenase (COX)-2-derived thromboxane B 2 and 6-keto PGF 1␣ and the COX-1-derived 12(S)-hydroxy-5-cis-8,10-transheptadecatrienoic acid was not significantly reduced. In carrageenan-induced rat pleurisy, YS121 (1.5 mg/kg i.p.) blocked exudate formation and leukocyte infiltration accompanied by reduced pleural levels of PGE 2 and leukotriene B 4 but also of 6-keto PGF 1␣ . Taken together, these results indicate that YS121 is a promising inhibitor of mPGES-1 with anti-inflammatory efficiency in human whole blood as well as in vivo.Prostaglandins (PGs) are potent lipid mediators that promote inflammatory reactions but also possess homeostatic functions (Funk, 2001). Their biosynthesis involves oxygenation of arachidonic acid by cyclooxygenase (COX)-1 or -2 to PGH 2 and further conversion by PG synthases to the respective PGs (Funk, 2001). Inhibition of COX-1 and -2 by nonsteroidal anti-inflammatory drugs and selective suppression of COX-2 by coxibs are common and effective strategies for the therapy of inflammatory disorders, fever, and pain, but their long-term use is associated with severe side effects (Rainsford, 2007). Unselective COX-1/2 inhibitors may cause gastric toxicity, whereas an increased cardiovascular risk in This work was supported in part by Carl Zeiss GmbH (to C.P.). Article, publication date, and citation information can be found at

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“…In a study by Wisniewska et al, imidazo[1,2-a]pyridine-3-yl-amine analog (EP6, II) was evaluated as a 5-LOX inhibitor 13 . On the other hand, a series of quinolinebased compounds were reported as potent inhibitors of LOX [14][15][16][17][18] . These findings convinced us to design a new core containing quinoline and imidazole-fused system as a new 15-LOX inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Quinoline-based imidazole-fused heterocycles as new inhibitors of 15-lipoxygenase

Dianat

Moghimi

Mahdavi

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 2-chloro-quinoline-based imidazopyridines 6a-l and imidazothiazoles 6m-o bearing a bulky alkylamine side chain were synthesized as soybean 15-LOX inhibitors. The target compounds 6a-o were prepared via one-pot reaction of 2-chloroquinoline-3-carbaldehyde (3), heteroaromatic amidine 4, and alkyl isocyanides 5, in the presence of NH 4 Cl. All compounds showed significant anti-15-LOX activity (IC 50 values 40 mM). Among the title compounds, the imidazo[2,1-b]thiazole derivative 6n bearing a tert-butylamine moiety showed the highest activity against soybean 15-LOX enzyme.

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Novel and Potent Inhibitors of 5-Lipoxygenase Product Synthesis Based on the Structure of Pirinixic Acid

Cited by 25 publications

References 21 publications

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

The Molecular Pharmacology and In Vivo Activity of 2-(4-Chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a Dual Inhibitor of Microsomal Prostaglandin E₂ Synthase-1 and 5-Lipoxygenase

Quinoline-based imidazole-fused heterocycles as new inhibitors of 15-lipoxygenase

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Novel and Potent Inhibitors of 5-Lipoxygenase Product Synthesis Based on the Structure of Pirinixic Acid

Cited by 25 publications

References 21 publications

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

The Molecular Pharmacology and In Vivo Activity of 2-(4-Chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a Dual Inhibitor of Microsomal Prostaglandin E2 Synthase-1 and 5-Lipoxygenase

Quinoline-based imidazole-fused heterocycles as new inhibitors of 15-lipoxygenase

Contact Info

Product

Resources

About

The Molecular Pharmacology and In Vivo Activity of 2-(4-Chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a Dual Inhibitor of Microsomal Prostaglandin E₂ Synthase-1 and 5-Lipoxygenase