Novel 1,3,4-oxadiazole derivatives as highly potent microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors.

Selective inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is implicated as a new therapeutic modality for the development of new-generation anti-inflammatory drugs. Here, we present the discovery of new and potent inhibitors of human mPGES-1, i.e., compounds 13, 15-25, 29-30 with IC50 values in the range of 5.6-82.3 nM in a cell-free assay of prostaglandin (PG)E2 formation. We also demonstrate that 20 (TG554, IC50 = 5.6 nM) suppresses leukotriene (LT) biosynthesis at low µM concentrations, providing a benchmark compound that dually intervenes with inflammatory PGE2 and LT biosynthesis. Comprehensive lipid mediator (LM) metabololipidomics with activated human monocyte-derived macrophages showed that TG554 selectively inhibits inflammatory PGE2 formation over all cyclooxygenase (COX)-derived prostanoids, does not cause substrate shunting towards 5-lipoxygenase (5-LOX) pathway, and does not interfere with the biosynthesis of the specialized pro-resolving mediators as observed with COX inhibitors, providing a new chemotype for effective and safer anti-inflammatory drug development.

Targeting TACC3 Induces Immunogenic Cell Death and Enhances T-DM1 Response in HER2-Positive Breast Cancer.

Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells, T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pretreatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of antitumor CD8+ T cells in posttreatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1-resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression whereas nonresponders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacologic inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the antitumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance. SIGNIFICANCE: Loss of induction of immunogenic cell death in response to T-DM1 leads to resistance that can be overcome by targeting TACC3, providing an attractive strategy to improve the efficacy of T-DM1.

Substituted 1,2,4-Triazoles as Novel and Selective Inhibitors of Leukotriene Biosynthesis Targeting 5-Lipoxygenase-Activating Protein.

5-Lipoxygenase-activating protein (FLAP) is a regulator of cellular leukotriene biosynthesis, which governs the transfer of arachidonic acid (AA) to 5-lipoxygenase for efficient metabolism. Here, the synthesis and FLAP-antagonistic potential of fast synthetically accessible 1,2,4-triazole derivatives based on a previously discovered virtual screening hit compound is described. Our findings reveal that simple structural variations on 4,5-diaryl moieties and the 3-thioether side chain of the 1,2,4-triazole scaffold markedly influence the inhibitory potential, highlighting the significant chemical features necessary for FLAP antagonism. Comprehensive metabololipidomics analysis in activated FLAP-expressing human innate immune cells and human whole blood showed that the most potent analogue 6x selectively suppressed leukotriene B4 formation evoked by bacterial exotoxins without affecting other branches of the AA pathway. Taken together, the 1,2,4-triazole scaffold is a novel chemical platform for the development of more potent FLAP antagonists, which warrants further exploration for their potential as a new class of anti-inflammatory agents.

Reviving immunogenic cell death upon targeting TACC3 enhances T-DM1 response in HER2-positive breast cancer.

Immunogenic cell death (ICD), an immune-priming form of cell death, has been shown to be induced by several different anti-cancer therapies. Despite being the first and one of the most successful antibody-drug conjugates (ADCs) approved for refractory HER2-positive breast cancer, little is known if response and resistance to trastuzumab emtansine (T-DM1) involves ICD modulation that can be leveraged to enhance T-DM1 response. Here, we report that T-DM1 induces spindle assembly checkpoint (SAC)-dependent ICD in sensitive cells by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which are lost in resistance. Accordingly, an ICD-related gene signature correlates with clinical response to T-DM1-containing therapy. We found that transforming acidic coiled-coil containing 3 (TACC3) is overexpressed in T-DM1 resistant cells, and that T-DM1 responsive patients have reduced TACC3 protein while the non-responders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacological inhibition of TACC3 revives T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition elicits ICD in vivo shown by vaccination assay, and it potentiates T-DM1 by inducing dendritic cell (DC) maturation and enhancing infiltration of cytotoxic T cells in the human HER2-overexpressing MMTV.f.huHER2#5 (Fo5) transgenic model. Together, our results show that ICD is a key mechanism of action of T-DM1 which is lost in resistance, and that targeting TACC3 restores T-DM1-mediated ICD and overcomes resistance.

Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification.

Centrosome amplification (CA) is a hallmark of cancer that is strongly associated with highly aggressive disease and worse clinical outcome. Clustering extra centrosomes is a major coping mechanism required for faithful mitosis of cancer cells with CA that would otherwise undergo mitotic catastrophe and cell death. However, its underlying molecular mechanisms have not been fully described. Furthermore, little is known about the processes and players triggering aggressiveness of cells with CA beyond mitosis. Here, we identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) to be overexpressed in tumors with CA, and its high expression is associated with dramatically worse clinical outcome. We demonstrated, for the first time, that TACC3 forms distinct functional interactomes regulating different processes in mitosis and interphase to ensure proliferation and survival of cancer cells with CA. Mitotic TACC3 interacts with the Kinesin Family Member C1 (KIFC1) to cluster extra centrosomes for mitotic progression, and inhibition of this interaction leads to mitotic cell death via multipolar spindle formation. Interphase TACC3 interacts with the nucleosome remodeling and deacetylase (NuRD) complex (HDAC2 and MBD2) in nucleus to inhibit the expression of key tumor suppressors (e.g., p21, p16 and APAF1) driving G1/S progression, and its inhibition blocks these interactions and causes p53-independent G1 arrest and apoptosis. Notably, inducing CA by p53 loss/mutation increases the expression of TACC3 and KIFC1 via FOXM1 and renders cancer cells highly sensitive to TACC3 inhibition. Targeting TACC3 by guide RNAs or small molecule inhibitors strongly inhibits growth of organoids and breast cancer cell line- and patient-derived xenografts with CA by induction of multipolar spindles, mitotic and G1 arrest. Altogether, our results show that TACC3 is a multifunctional driver of highly aggressive breast tumors with CA and that targeting TACC3 is a promising approach to tackle this disease.

Benzoxazolone-5-Urea Derivatives as Human Soluble Epoxide Hydrolase (sEH) Inhibitors.

Inhibition of soluble epoxide hydrolase (sEH) is indicated as a new therapeutic modality against a variety of inflammatory diseases, including metabolic, renal, and cardiovascular disorders. In our ongoing research on sEH inhibitors, we synthesized novel benzoxazolone-5-urea analogues with highly potent sEH inhibitory properties inspired by the crystallographic fragment scaffolds incorporating a single H-bond donor/acceptor pair. The tractable SAR results indicated that the aryl or benzyl fragments flanking the benzoxazolone-urea scaffold conferred potent sEH inhibition, and compounds 31-39 inhibited the sEH activity with IC50 values in the range of 0.39-570 nM. Docking studies and molecular dynamics simulations with the most potent analogue 33 provided valuable insights into potential binding interactions of the inhibitor in the sEH binding region. In conclusion, benzoxazolone-5-ureas furnished with benzyl groups on the urea function can be regarded as novel lead structures, which allow the development of advanced analogues with enhanced properties against sEH.

Vicinal Diaryl-Substituted Isoxazole and Pyrazole Derivatives with In Vitro Growth Inhibitory and In Vivo Antitumor Activity.

The vicinal diaryl heterocyclic framework has been widely used for the development of compounds with significant bioactivities. In this study, a series of diaryl heterocycles were designed and synthesized based on an in-house diaryl isoxazole derivative (9), and most of the newly synthesized derivatives demonstrated moderate to good antiproliferative activities against a panel of hepatocellular carcinoma and breast cancer cells, exemplified with the diaryl isoxazole 11 and the diaryl pyrazole 85 with IC50 values in the range of 0.7-9.5 µM. Treatments with both 11 and 85 induced apoptosis in these tumor cells, and they displayed antitumor activity in vivo in the Mahlavu hepatocellular carcinoma and the MDA-MB-231 breast cancer xenograft models, indicating that these compounds could be considered as leads for further development of antitumor agents. Important structural features of this compound class for the antitumor activity have also been proposed, which warrant further exploration to guide the design of new and more potent diaryl heterocycles.

Quinazoline-4(3H)-one-7-carboxamide Derivatives as Human Soluble Epoxide Hydrolase Inhibitors with Developable 5-Lipoxygenase Activating Protein Inhibition.

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), which are endowed with beneficial biological activities as they reduce inflammation, regulate endothelial tone, improve mitochondrial function, and decrease oxidative stress. Therefore, inhibition of sEH for maintaining high EET levels is implicated as a new therapeutic modality with broad clinical applications for metabolic, renal, and cardiovascular disorders. In our search for new sEH inhibitors, we designed and synthesized novel amide analogues of the quinazolinone-7-carboxylic acid derivative 5, a previously discovered 5-lipoxygenase-activating protein (FLAP) inhibitor, to evaluate their potential for inhibiting sEH. As a result, we identified new quinazolinone-7-carboxamides that demonstrated selective sEH inhibition with decreased FLAP inhibitor properties. The tractable SAR results indicated that the amide and thiobenzyl fragments flanking the quinazolinone nucleus are critical features governing the potent sEH inhibition, and compounds 34, 35, 37, and 43 inhibited the sEH activity with IC50 values of 0.30-0.66 µM. Compound 34 also inhibited the FLAP-mediated leukotriene biosynthesis (IC50 = 2.91 µM). In conclusion, quinazolinone-7-carboxamides can be regarded as novel lead structures, and newer analogues with improved efficiency against sEH along with or without FLAP inhibition can be generated.

The 1,2,3-triazole 'all-in-one' ring system in drug discovery: a good bioisostere, a good pharmacophore, a good linker, and a versatile synthetic tool.

INTRODUCTION: The 1,2,3-triazole ring occupies an important space in medicinal chemistry due to its unique structural properties, synthetic versatility and pharmacological potential making it a critical scaffold. Since it is readily available through click chemistry for creating compound collections against various diseases, it has become an emerging area of interest for medicinal chemists. AREAS COVERED: This review article addresses the unique properties of the1,2,3-triazole nucleus as an intriguing ring system in drug discovery while focusing on the most recent medicinal chemistry strategies exploited for the design and development of 1,2,3-triazole analogs as inhibitors of various biological targets. EXPERT OPINION: Evidently, the 1,2,3-triazole ring with unique structural features has enormous potential in drug design against various diseases as a pharmacophore, a bioisoster or a structural platform. The most recent evidence indicates that it may be more emerging in drug molecules in near future along with an increasing understanding of its prominent roles in drug structures. The synthetic feasibility and versatility of triazole chemistry make it certainly ideal for creating compound libraries for more constructive structure-activity relationship studies. However, more comparative and target-specific studies are needed to gain a deeper understanding of the roles of the 1,2,3-triazole ring in molecular recognition.[Figure: see text].

Development and molecular modeling studies of new thiadiazole piperazine urea derivatives as potential fatty acid amide hydrolase inhibitors.

A series of novel piperazine urea derivatives with thiadiazole moieties were designed, synthesized, and investigated for their inhibition potential against human fatty acid amide hydrolase (hFAAH). The urea derivatives possessing p-chlorophenylthiadiazole and benzylpiperazine fragments (19-22) were effective inhibitors of hFAAH. Notably, compounds with 4-chlorobenzyl (19) and 4-fluorobenzyl (20) tails at the piperazine side were identified as the most active inhibitors with IC50 values of 0.13 and 0.22 µM, respectively. The preincubation test of 19 was in agreement with the irreversible binding mechanism. Molecular docking was performed to explore the potential binding interactions with key amino acid residues at the FAAH active site. These newly identified inhibitors could serve as leads for the further development of potent and selective FAAH inhibitors for FAAH-associated diseases.

Discovery and Optimization of Piperazine Urea Derivatives as Soluble Epoxide Hydrolase (sEH) Inhibitors.

Soluble epoxide hydrolase (sEH) is implicated as a potential therapeutic target for inflammation-related pathologies in the context of cardiovascular, central nervous system and metabolic diseases. In our search for novel sEH inhibitors, we designed and synthesized novel analogs of the piperazine urea derivative 4, a previously discovered dual microsomal prostaglandin E2 synthase-1 (mPGES-1)/soluble epoxide hydrolase (sEH) inhibitor, to evaluate their potential as sEH inhibitors. We identified two 1,3,4-oxadiazol-5-one and -thione congeners (compounds 19 and 20), which demonstrated selective sEH inhibition with IC50 values in the two-digit nanomolar range (42 and 56 nM, respectively). These results suggest that the installation of terminal 1,3,4-oxadiazol-5-one/thione functions to the benzyl end can be regarded as a promising secondary pharmacophore in addition to the urea group for sEH inhibition, and compound 19 can be regarded as novel lead structure for further optimization of improved sEH inhibitors.

A Series of Thiadiazolyl-Benzenesulfonamides Incorporating an Aromatic Tail as Isoform-Selective, Potent Carbonic Anhydrase II/XII Inhibitors.

We describe the synthesis of a series of thiadiazolyl-benzenesulfonamide derivatives carrying an aromatic tail linked by an amide linker (12-34), as human carbonic anhydrase (hCA) inhibitors. These thiadiazol derivatives were evaluated against four physiologically relevant CA isoforms (hCA I, II, IX, and XII), and demonstrated intriguing inhibitory activity against CA II with Ki values in the range of 2.4-31.6 nM. Besides hCA II, also hCA XII activity was potently inhibited by some of the derivatives (Ki =1.5-88.5 nM), producing dual inhibitors of both isoforms. Notably, compound 17 was the most potent dual CA II (Ki =3.1 nM) and XII (Ki =1.5 nM) inhibitor with a significant selectivity ratio over CA I and IX isoforms. In conclusion, although all compounds exhibited preferential activity towards hCA II, the nature of the substituents at the tail part of the main scaffold influenced the activity and selectivity toward other isoforms.

Shifting the Biosynthesis of Leukotrienes Toward Specialized Pro-Resolving Mediators by the 5-Lipoxygenase-Activating Protein (FLAP) Antagonist BRP-201.

BACKGROUND AND PURPOSE: Lipid mediators (LM) play crucial roles in the complex inflammation process with respect to initiation, maintenance, and resolution. Proinflammatory leukotrienes (LTs), generated by 5-lipoxygenase (LOX) and the 5-LOX-activating protein (FLAP), initiate and maintain inflammation while specialized pro-resolving mediators (SPMs) formed by various LOXs as key enzymes promote inflammation resolution and the return to homeostasis. Since 5-LOX also contributes to SPM biosynthesis, smart pharmacological manipulation of the 5-LOX pathway and accompanied activation of 12-/15-LOXs may accomplish suppression of LT formation but maintain or even elevate SPM formation. Here, we demonstrated that the FLAP antagonist BRP-201 possesses such pharmacological profile and causes a switch from LT toward SPM formation. METHODS AND RESULTS: Comprehensive LM metabololipidomics with activated human monocyte-derived macrophages (MDM) of M1 or M2 phenotype showed that BRP-201 strongly inhibits LT formation induced by bacterial exotoxins. In parallel, SPM levels and 12/15-LOX-derived products were markedly elevated, in particular in M2-MDM. Intriguingly, in unstimulated MDM, BRP-201 induced formation of 12/15-LOX products including SPM and caused 15-LOX-1 subcellular redistribution without affecting 5-LOX. Experiments with HEK293 cells stably expressing either 5-LOX with or without FLAP, 15-LOX-1 or 15-LOX-2 confirmed suppression of 5-LOX product formation due to FLAP antagonism by BRP-201 but activated 15-LOX-1 in the absence of FLAP. Finally, in zymosan-induced murine peritonitis, BRP-201 (2 mg/kg, ip) lowered LT levels but elevated 12/15-LOX products including SPMs. CONCLUSION: BRP-201 acts as FLAP antagonist but also as 12/15-LOX activator switching formation of pro-inflammatory LTs toward inflammation-resolving SPM, which reflects a beneficial pharmacological profile for intervention in inflammation.

Novel potent benzimidazole-based microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors derived from BRP-201 that also inhibit leukotriene C4 synthase.

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is recognized as a promising therapeutic target for next-generation anti-inflammatory drugs to treat inflammatory diseases. In this study, we report the identification of new, potent and selective inhibitors of human mPGES-1 such as compounds 10, 31 and 49 with IC50 of 0.03-0.09 µM in a cell-free assay of PGE2 production. Compound 10 and 49 also inhibited leukotriene C4 synthase (LTC4S) at sub-µM concentrations (IC50 = 0.7 and 0.4 µM, respectively), affording compounds dually targeting inflammatory PGE2 and cysteinyl leukotriene (cys-LT) biosynthesis. However, compound 31 showed substantial selectivity towards mPGES-1 (IC50 = 0.03 µM) with a decreased inhibitory activity on LTC4S (IC50 = 2.8 µM), and also on other related targets such as FLAP and 5-LO. These oxadiazole thione-benzimidazole derivatives warrant further exploration of new and alternative analogs that may lead to the identification of novel derivatives with potent anti-inflammatory properties.

Ethoxy acetalated dextran-based nanocarriers accomplish efficient inhibition of leukotriene formation by a novel FLAP antagonist in human leukocytes and blood.

Leukotrienes are pro-inflammatory lipid mediators generated by 5-lipoxygenase aided by the 5-lipoxygenase-activating protein (FLAP). BRP-201, a novel benzimidazole-based FLAP antagonist, inhibits leukotriene biosynthesis in isolated leukocytes. However, like other FLAP antagonists, BRP-201 fails to effectively suppress leukotriene formation in blood, which limits its therapeutic value. Here, we describe the encapsulation of BRP-201 into poly(lactide-co-glycolide) (PLGA) and ethoxy acetalated dextran (Ace-DEX) nanoparticles (NPs), aiming to overcome these detrimental pharmacokinetic limitations and to enhance the bioactivity of BRP-201. NPs loaded with BRP-201 were produced via nanoprecipitation and the physicochemical properties of the NPs were analyzed in-depth using dynamic light scattering (size, dispersity, degradation), electrophoretic light scattering (effective charge), NP tracking analysis (size, dispersity), scanning electron microscopy (size and morphology), UV-VIS spectroscopy (drug loading), an analytical ultracentrifuge (drug release, degradation kinetics), and Raman spectroscopy (chemical attributes). Biological assays were performed to study cytotoxicity, cellular uptake, and efficiency of BRP-201-loaded NPs versus free BRP-201 to suppress leukotriene formation in primary human leukocytes and whole blood. Both PLGA- and Ace-DEX-based NPs were significantly more efficient to inhibit leukotriene formation in neutrophils versus free drug. Whole blood experiments revealed that encapsulation of BRP-201 into Ace-DEX NPs strongly increases its potency, especially upon pro-longed (≥ 5 h) incubations and upon lipopolysaccharide-challenge of blood. Finally, intravenous injection of BRP-201-loaded NPs significantly suppressed leukotriene levels in blood of mice in vivo. These results reveal the feasibility of our pharmacological approach using a novel FLAP antagonist encapsulated into Ace-DEX-based NPs with improved efficiency in blood to suppress leukotriene biosynthesis.

Crystal structure and Hirshfeld surface analysis of 4-(4-chloro-phen-yl)-5-methyl-3-{4-[(2-methyl-phen-yl)meth-oxy]phen-yl}-1,2-oxazole.

In the title compound, C24H20ClNO2, the mean planes of 4-chloro-phenyl, 2-methyl-phenyl and phenyl-ene rings make dihedral angles of 62.8 (2), 65.1 (3) and 15.1 (2)°, respectively, with the 5-methyl-1,2-oxazole ring. In the crystal, mol-ecules are linked by inter-molecular C-H⋯N, C-H⋯Cl, C-H⋯π contacts and π-π stacking inter-actions between the phenyl-ene groups. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H⋯H (48.7%), H⋯C/C⋯H (22.2%), Cl⋯H/H⋯Cl (8.8%), H⋯O/O⋯H (8.2%) and H⋯N/N⋯H (5.1%) inter-actions.

Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells.

In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated potent to moderate cytotoxicity on all cell lines with IC50 values in the range of 0.09-11.7 µM. Further biological studies with 6a and 13d in HCC cells have shown that both compounds induced G1 or G2/M arrests resulting in apoptotic cell death. Subsequent analysis of proteins involved in cell cycle progression as well as proliferation of HCC cells revealed that 6a and 13d may affect cellular survival pathways differently depending on the mutation profiles of cells (p53 and PTEN), epidermal/mesenchymal characteristics, and activation of cell mechanisms through p53 dependent/independent pathways. Lastly, we have demonstrated the potential anti-stemness properties of these compounds in which the proportion of liver CSCs in Huh7 cells (CD133+/EpCAM+) were significantly reduced by 6a and 13d. Furthermore, both compounds caused a significant reduction in expression of stemness markers, NANOG or OCT4 proteins, in Mahlavu and Huh7 cells, as well as resulted in a decreased sphere formation capacity in Huh7 cells. Together, these novel isoxazole-piperazine derivatives may possess potential as leads for development of effective anti-cancer drugs against HCC cells with stem cell-like properties.

Simple heteroaryl modifications in the 4,5-diarylisoxazol-3-carboxylic acid scaffold favorably modulates the activity as dual mPGES-1/5-LO inhibitors with in vivo efficacy.

Microsomal prostaglandin E2 synthase-1 (mPGES-1), 5-lipoxygenase (5-LO) and 5- lipoxygenase-activating protein (FLAP) are key for biosynthesis of proinflammatory lipid mediators and pharmacologically relevant drug targets. In the present study, we made an attempt to explore the role of small heteroaromatic fragments on the 4,5-diarylisoxazol-3-carboxylic acid scaffold, which are selected to interact with focused regions in the active sites of mPGES-1, 5-LO and FLAP. We report that the simple structural variations on the benzyloxyaryl side-arm of the scaffold significantly influence the selectivity against mPGES-1, 5-LO and FLAP, enabling to produce multi-target inhibitors of these protein targets, exemplified by compound 18 (IC50 mPGES-1 = 0.16 µM; IC50 5-LO = 0.39 µM) with in vivo efficacy in animal model of inflammation. The computationally modeled binding structures of these new inhibitors for three targets provide clues for rational design of modified structures as multi-target inhibitors. In conclusion, the simple synthetic procedure, and the possibility of enhancing the potency of this class of inhibitors through structural modifications pave the way for further development of new multi-target inhibitors against mPGES-1, 5-LO and FLAP, with potential application as anti-inflammatory agents.