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ABSTRACT: A novel set of dual γ-secretase/PPARγ modulators characterized by a 2-benzyl hexanoic acid scaffold is presented. Synthetic efforts were focused on the variation of the substitution pattern of the central benzene. Finally, we obtained a new class of 2,5-disubstituted 2-benzylidene hexanoic acid derivatives, which act as dual γ-secretase/PPARγ modulators in the low micromolar range. We have explored broad SAR and successfully improved the dual pharmacological activity and the selectivity profile against potential off-targets such as NOTCH and COX. Compound 17 showed an IC(50) Aβ42=2.4 μM and an EC(50) PPARγ=7.2 μM and could be a valuable tool to further evaluate the concept of dual γ-secretase/PPARγ modulators in animal models of Alzheimer's disease.
Bioorganic & medicinal chemistry 08/2011; 19(18):5372-82. · 2.82 Impact Factor
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ABSTRACT: Various inflammatory diseases are associated with the excessive formation of leukotrienes (LTs) and prostaglandins (PGs). Herein, we present a novel class of dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E(2) synthase-1 (mPGES-1), key enzymes in the formation of LTs and PGE(2), respectively. On the basis of the structure of 2-[(4,6-diphenethoxypyrimidin-2-yl)thio]hexanoic acid (1), we performed a detailed SAR analysis, and mechanistic studies were carried out to elucidate the mode of 5-LO inhibition. Interestingly, the pyrimidine ring including the thioether of 1 could be replaced by a simple benzyl or a benzylidene moiety yielding a novel series of bioactive 2-benzylidene- and 2-benzylhexanoic acids exemplified by 2-(2,3-diphenethoxybenzylidene)hexanoic acid, 29 (IC(50) 5-LO = 0.8 μM; mPGES-1 = 1.1 μM). Importantly, none of the novel bioactive derivatives strongly inhibited cyclooxygenase activities. Together, we provide novel promising lead compounds for the treatment of inflammatory diseases valuable for further investigations in vivo.
Journal of Medicinal Chemistry 06/2011; 54(13):4490-507. · 4.80 Impact Factor
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ABSTRACT: 5-Lipoxygenase (5-LO) and microsomal prostaglandin E₂ synthase (mPGES)-1 are key enzymes in the biosynthesis of leukotrienes and prostaglandin (PG)E₂, respectively, and are considered as valuable targets for the treatment of inflammatory diseases. Here, we present the identification of 2-mercaptohexanoic acid derivatives as dual inhibitors of 5-LO and mPGES-1. The lead compound 2(4-(3-biphenyloxypropoxy)phenylthio)hexanoic acid (21) inhibits human 5-LO and mPGES-1 in cell-free assays with an IC₅₀ = 3.5 and 2.2 μM, respectively, and suppresses 5-LO in intact cells with even a higher potency (IC₅₀=0.9 μM). Compound 21 (10 μM) neither significantly inhibited the related 12- or 15-LOs nor cyclooxygenase-1 and -2 or cytosolic phospholipase A₂. Based on the selective and potent inhibition of 5-LO and mPGES-1, further assessment of these 2-mercaptohexanoic acids in preclinical models of inflammation are warranted.
Bioorganic & medicinal chemistry 06/2011; 19(11):3394-401. · 2.82 Impact Factor
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ABSTRACT: Dual inhibition of microsomal prostaglandin E(2) synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic acid cascade. Herein, a class of α-naphthyl pirinixic acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC(50) mPGES-1=0.94 μM; IC(50) 5-LO=0.1 μM) showing the most favorable in vitro pharmacological profile.
Bioorganic & medicinal chemistry letters 03/2011; 21(5):1329-33. · 2.65 Impact Factor
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ABSTRACT: We present a novel class of dual modulators of gamma-secretase and peroxisome proliferator-activated receptor gamma (PPARgamma) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC(50)(Abeta42) = 22.8 microM, EC(50)(PPARgamma) = 8.3 microM). The modulation of both targets with approved drugs (i.e., amyloid-beta 42 (Abeta42)-lowering NSAIDs for gamma-secretase and glitazones for PPARgamma) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer's disease (AD). However, although NSAIDs and PPARgamma agonists share similar structural features, no druglike compounds with dual activities as gamma-secretase modulators (GSMs) and PPARgamma agonists have been designed so far. On the basis of our initial lead structure 8, we present the structure-activity relationships (SARs) of broad structural variations. A significant improvement was reached by the introduction of p-trifluoromethyl substituents at the phenyl residues yielding compound 16 (IC(50)(Abeta42) = 6.0 microM, EC(50)(PPARgamma) = 11.0 microM) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC(50)(Abeta42) = 5.1 microM, EC(50)(PPARgamma) = 6.6 microM).
Journal of Medicinal Chemistry 06/2010; 53(12):4691-700. · 4.80 Impact Factor
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ABSTRACT: We present a novel class of dual modulators of γ-secretase and peroxisome proliferator-activated receptor γ (PPARγ) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC50(Aβ42) = 22.8 μM, EC50(PPARγ) = 8.3 μM). The modulation of both targets with approved drugs (i.e., amyloid-β 42 (Aβ42)-lowering NSAIDs for γ-secretase and glitazones for PPARγ) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer’s disease (AD). However, although NSAIDs and PPARγ agonists share similar structural features, no druglike compounds with dual activities as γ-secretase modulators (GSMs) and PPARγ agonists have been designed so far. On the basis of our initial lead structure 8, we present the structure−activity relationships (SARs) of broad structural variations. A significant improvement was reached by the introduction of p-trifluoromethyl substituents at the phenyl residues yielding compound 16 (IC50(Aβ42) = 6.0 μM, EC50(PPARγ) = 11.0 μM) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC50(Aβ42) = 5.1 μM, EC50(PPARγ) = 6.6 μM).
05/2010;
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Andreas Koeberle,
Antonietta Rossi,
Heiko Zettl,
Carlo Pergola,
Friederike Dehm,
Julia Bauer, Christine Greiner,
Sina Reckel,
Christina Hoernig,
Hinnak Northoff,
Frank Bernhard,
Volker Dötsch,
Lidia Sautebin,
Manfred Schubert-Zsilavecz,
Oliver Werz
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ABSTRACT: 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 alpha-(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) = 3.4 muM), 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) = 10-14 muM). In lipopolysaccharide-stimulated human whole blood, PGE(2) formation was concentration dependently inhibited (IC(50) = 2 muM), whereas concomitant generation of the cyclooxygenase (COX)-2-derived thromboxane B(2) and 6-keto PGF(1alpha) and the COX-1-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic 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(1alpha). 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.
Journal of Pharmacology and Experimental Therapeutics 11/2009; 332(3):840-8. · 3.83 Impact Factor
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ABSTRACT: Pirinixic acid (Wy-14,643) is an agonist of the peroxisome proliferator-activated receptor (PPAR) subtype alpha exhibiting beneficial effects in various inflammation-related processes in a slow, long-termed fashion. We recently showed that alpha-substituted pirinixic acid derivatives are agonists of PPAR alpha and act as dual inhibitors of 5-lipoxygenase (5-LO, EC 1.13.11.34) and the microsomal prostaglandin E(2) synthase-1 (EC 5.3.99.3). Here, we explored short-term effects of alpha-substituted pirinixic acid derivatives on typical neutrophil functions evoked by the agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP) including leukotriene formation, generation of reactive oxygen species, and release of human leukocyte elastase (EC 3.4.21.37), and we investigated the modulation of related signalling pathways. Pirinixic acid derivatives that are substituted with alkyl residues in alpha-position of the carboxylic group and with a 6-aminoquinoline residue at the pyrimidine moiety cause inhibition of leukotriene formation, reactive oxygen species formation, and leukocyte elastase release in response to fMLP. In parallel, Ca(2+) mobilisation and the phosphorylation (activation) of p38 mitogen-activated protein kinase was significantly reduced, whereas phosphorylation of the extracellular signal-regulated kinase-2 was unaffected. Pirinixic acid itself was not or only marginally active in all these assays. Conclusively, targeted structural modification of pirinixic acid leads to bioactive compounds that display immediate anti-inflammatory properties in human neutrophils with potential therapeutic value.
European journal of pharmacology 09/2009; 619(1-3):1-7. · 2.59 Impact Factor
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ABSTRACT: Dual inhibition of the prostaglandin (PG) and leukotriene (LT) biosynthetic pathway is supposed to be superior over single interference, both in terms of efficacy and side effects. Here, we present a novel class of dual microsomal PGE(2) synthase-1/5-lipoxygenase (5-LO) inhibitors based on the structure of pirinixic acid [PA, 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)acetic acid, compound 1]. Target-oriented structural modification of 1, particularly alpha substitution with extended n-alkyl or bulky aryl substituents and concomitant replacement of the 2,3-dimethylaniline by a biphenyl-4-yl-methane-amino residue, resulted in potent suppression of mPGES-1 and 5-LO activity, exemplified by 2-(4-(biphenyl-4-ylmethylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (7b, IC(50) = 1.3 and 1 microM, respectively). Select compounds also potently reduced PGE(2) and 5-LO product formation in intact cells. Importantly, inhibition of cyclooxygenases-1/2 was significantly less pronounced. Taken together, these pirinixic acid derivatives constitute a novel class of dual mPGES-1/5-LO inhibitors with a promising pharmacological profile and a potential for therapeutic use.
Journal of Medicinal Chemistry 12/2008; 51(24):8068-76. · 4.80 Impact Factor
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ABSTRACT: A novel class of potent 5-lipoxygenase (5-LO) product synthesis inhibitors based on the structure of pirinixic acid (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid, compound 1) is presented. Systematic profiling of 1, i.e., esterification of the carboxylic acid, alpha-substitution, and replacement of the o-dimethylaniline by 6-aminoquinoline, leads to potent suppressors of 5-LO product formation in activated polymorphonuclear leukocytes, exemplified by ethyl 2-[4-chloro-6-(quinoline-6-ylamino)-pyrimidin-2-ylsulfanyl]octane-1-carboxylate (6d, IC50 = 0.6 microM). These derivatives may possess potential for intervention with inflammatory and allergic diseases.
Journal of Medicinal Chemistry 10/2008; 51(17):5449-53. · 4.80 Impact Factor
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ABSTRACT: Carnosic acid (CA) and carnosol (CS) are phenolic diterpenes present in several labiate herbs like Rosmarinus officinalis (Rosemary) and Salvia officinalis (Sage). Extracts of these plants exhibit anti-inflammatory properties, but the underlying mechanisms are largely undefined. Recently, we found that CA and CS activate the peroxisome proliferator-activated receptor gamma, implying an anti-inflammatory potential on the level of gene regulation. Here we address short-term effects of CA and CS on typical functions of human polymorphonuclear leukocytes (PMNL). We found that (I), CA and CS inhibit the formation of pro-inflammatory leukotrienes in intact PMNL (IC(50)=15-20 microM [CA] and 7 microM [CS], respectively) as well as purified recombinant 5-lipoxygenase (EC number 1.13.11.34, IC(50)=1 microM [CA] and 0.1 microM [CS], respectively), (II) both CA and CS potently antagonise intracellular Ca(2+) mobilisation induced by a chemotactic stimulus, and (III) CA and CS attenuate formation of reactive oxygen species and the secretion of human leukocyte elastase (EC number 3.4.21.37). Together, our findings provide a pharmacological basis for the anti-inflammatory properties reported for CS- and CA-containing extracts.
Biochemical pharmacology 08/2008; 76(1):91-7. · 4.25 Impact Factor
