Potent 5-lipoxygenase Inhibitor Research Articles

Sinapic acid phenethyl ester as a potent selective 5-lipoxygenase inhibitor: Synthesis and structure-activity relationship.

Given the hepatotoxicity and an unfavorable pharmacokinetic profile of zileuton (Zyflo® ), currently the only approved and clinically used 5-Lipoxygenase (5-LO) inhibitor, the search for potent and safe 5-LO inhibitors is highly demanded. The action of several phenolic acid phenethyl esters as potential 5-Lipoxygenase (5-LO) inhibitors has been investigated. For this purpose, a series of 14 phenethyl esters was synthesized and their impact on 5-LO inhibition was evaluated. The effects of position and number of hydroxyl and methoxy groups on the phenolic acid were investigated. The shortening of the linker between the carbonyl and the catechol moiety as well as the presence of the α,β-unsaturated carbonyl group was also explored. The sinapic acid phenethyl ester (10), which can be named SAPE (10) by analogy to caffeic acid phenethyl ester (CAPE), inhibited 5-LO in a concentration-dependent manner and outperformed both zileuton (1) and CAPE (2). With an IC50 of 0.3μm, SAPE (10) was threefold more potent than CAPE (2) and 10-fold more potent than zileuton (1), the only 5-LO inhibitor approved for clinical use. Unlike CAPE (2), SAPE (10) had no effect on 12-lipoxygenase (12-LO) and less effect on cyclooxygenase 1 (COX-1) which makes it a more selective 5-LO inhibitor.

Novel 6- and 7-Substituted Coumarins with Inhibitory Action against Lipoxygenase and Tumor-Associated Carbonic Anhydrase IX.

A series of carboxamide derivatives of 6- and 7-substituted coumarins have been prepared by an original procedure starting from the corresponding 6- or 7-hydroxycoumarins which were alkylated with ethyl iodoacetate, and the obtained ester was converted to the corresponding carboxylic acids which were thereafter reacted with a series of aromatic/aliphatic/heterocyclic amines leading to the desired amides. The new derivatives were investigated as inhibitors of two enzymes, human carbonic anhydrases (hCAs) and soy bean lipoxygenase (LOX). Compounds 4a and 4b were potent LOX inhibitors, whereas many effective hCA IX inhibitors (KIs in the range of 30.2–30.5 nM) were detected in this study. Two compounds, 4b and 5b, showed the phenomenon of dual inhibition. Furthermore, these coumarins did not significantly inhibit the widespread cytosolic isoforms hCA I and II, whereas they were weak hCA IV inhibitors, making them hCA IX-selective inhibitors. As hCA IX and LOX are validated antitumor targets, these results are promising for the investigation of novel drug targets involved in tumorigenesis.

Substituted furans as potent lipoxygenase inhibitors: Synthesis, in vitro and molecular docking studies

A number of 2-methyl-4-(2-oxo-2-phenyl-ethyl)-5-phenyl-furan-3-carboxylic acid alkyl ester derivatives (3a–j) were synthesized and evaluated for their in vitro inhibitory activity on soybean lipoxygenase enzyme. Among the screened compounds, 5-(4-bromo-phenyl)-4-[2-(4-bromo-phenyl)-2-oxo-ethyl]-2-methyl-furan-3-carboxylic acid methyl ester (3g) has been found to exhibit potent inhibitory activity with IC5012.8μM using nordihydroguaiaretic acid (NDGA) as standard. Molecular modeling was employed for better understanding of the binding between compounds and soybean lipoxygenase enzyme. The predicted binding energy values correlated well with the observed in vitro data.

Optimization of benzoquinone and hydroquinone derivatives as potent inhibitors of human 5-lipoxygenase

Aiming to assess the biological activities of synthetic 1,4-benzoquinones, we previously synthesized different libraries of benzoquinones with lipophilic and bulky alkyl- or aryl-substituents that inhibited 5-lipoxygenase (5-LO). The high potency of 4,5-dimethoxy-3-alkyl-1,2-benzoquinones on 5-LO led to the idea to further modify the structures and thus to improve the inhibitory potential in vitro and in vivo as well as to investigate SARs. Systematic structural optimization through accurate structure-based design resulted in compound 30 (3-tridecyl-4,5-dimethoxybenzene-1,2-diol), an ubiquinol derivative that exhibited the strongest anti-inflammatory effect, with a 10-fold improved 5-LO inhibitory activity (IC50 = 28 nM) in activated neutrophils. Moreover, 30 significantly reduced inflammatory reactions in the carrageenan-induced mouse paw oedema and in zymosan-induced peritonitis in mice. Compound 30 (1 mg/kg, i.p.) potently suppressed the levels of cysteinyl-LTs 30 min after zymosan, outperforming zileuton at a dose of 10 mg/kg. The binding patterns of the quinone- and hydroquinone-based 5-LO inhibitors were analyzed by molecular docking. Together, we elucidated the optimal alkyl chain pattern of quinones and corresponding hydroquinones and reveal a series of highly potent 5-LO inhibitors with effectiveness in vivo that might be useful as anti-inflammatory drugs.

Preliminary structure-activity relationship studies on some novel s-substituted aliphatic analogues of 5-{1-[(4- chlorophenyl) sulfonyl]-3-piperidinyl}-1, 3, 4-oxadiazol-2-yl sulfide

Purpose : To study the structure-activity relationships of synthetic multifunctional sulfides through evaluation of lipoxygenase and anti-bacterial activities. Methods : S-substituted derivatives of the parent compound 5-(1-(4- chlorophenylsulfonyl) piperidin-3- yl)-1, 3, 4-oxadiazole-2-thiol were synthesized through reaction with different saturated and unsaturated alkyl halides in DMF medium, with NaH catalyst. Spectral characterization of each derivative was carried out with respect to IR, 1H - NMR, 13C - NMR and EI - MS. The lipoxygenase inhibitory and antibacterial activities of the derivatives were determined using standard procedures . Results : Compound 5e exhibited higher lipoxygenase inhibitory potential than the standard (Baicalein®), with % inhibition of 94.71 ± 0.45 and IC50 of 20.72 ± 0.34 μmoles/L. Compound 5b showed significant antibacterial potential against all the bacterial strains with % inhibition ranging from 62.04 ± 2.78, 69.49 ± 0.41, 63.38 ± 1.97 and 59.70 ± 3.70 to 78.32 ± 0.41, while MIC ranged from 8.18 ± 2.00, 10.60 ± 1.83, 10.84 ± 3.00, 9.81 ± 1.86 and 11.73 ± 5.00 μmoles/L for S. typhi, E. coli, P. aeruginosa, B. subtilis and S. aureus, respectively. Compounds 5d, 5e and 5g showed good antibacterial activity against S. typhi and B. subtilis bacterial strains. Conclusion : The results suggest that compound 5e bearing n-pentyl group is a potent lipoxygenase inhibitor, while compound 5b with n-propyl substitution is a strong antibacterial agent. In addition, compounds 5d, 5e and 5g bearing n-butyl, n-pentyl and n-octyl groups, respectively, are good antibacterial agents against S. typhi and B. subtilis. Keywords : Sulfides, Antibacterial activity, Lipoxygenase activity, Spectral analysis

Miconidin Acetate and Primin as Potent 5-Lipoxygenase Inhibitors from Brazilian Eugenia hiemalis (Myrtaceae)

This paper describes the isolation and identification of primin and miconidin acetate as metabolites from the flower bud extract of Eugenia hiemalis as well as the anti-inflammatory activity of miconidin acetate by inhibition of 5-lipoxygenase. Miconidin acetate inhibited leukotriene B4 formation catalyzed by the human recombinant enzyme (IC50 = 0.3 ± 0.17 µM) more than primin (IC50 = 1.4 ± 0.6 µM) and zileuton (IC50 = 1.1 ± 0.7 µM). Miconidin acetate (20 µM) inhibited LTB4 formation to an extent of 59 ± 12 % in vitro using a cell-based assay, comparable to the positive control zileuton (69 ± 12 % inhibition at a concentration of 10 µM). The binding modes of miconidin acetate were further evaluated in silico by molecular docking to the human 5-lipoxygenase crystal structure. The hydroxyl group was predicted to form a hydrogen bond with the terminal Ile676, while the pentyl moiety occupied the hydrophobic substrate channel. The obtained results show that flower buds of E. hiemalis are an interesting source of anti-inflammatory compounds, mainly of miconidin acetate.

An Approach to Computer Aided Drug Design of some Bioactive Cinnamoyl Hydrazones, In Silico and Docking Studies as Possible COX-2 Selective Inhibitors

Recently structural analogue-based drug discovery has become an important tool for designing more potent drugs. This study uses SAR, pharmacophore study and structural analogue-based novel drugs to design selective inhibitor molecules using internet-based tools. Substituted acyl hydrazones are known for wide variety of biological activities, such as analgesic, anti–inflammatory, anti-microbial, anti-convulsant, anti-platelet, anti-tubercular, antiviral, schistomiasis and anti-tumoral activities. In the last decade several cinnamic acid derivatives were reported as potent lipoxygenase inhibitors, antioxidants and anti-inflammatory agents. We found it interesting to combine these particular molecules and design cinnamoyl hydrazones, a series of N-[(1E)-2-substituted phenyl-1-{N'-[(1E)-phenyl methylidene] hydrazine carbonyl} eth-1-en-1-yl] benzamides. The designed compounds were predicted for their drug likeness and oral bioavailability. Selected compounds were docked with COX-2 enzyme and found that they were showing similar interactions as that of SC-558, 1000 time selective standard COX-2 inhibitor.

Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase

Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders.

Esters of some non-steroidal anti-inflammatory drugs with cinnamyl alcohol are potent lipoxygenase inhibitors with enhanced anti-inflammatory activity.

Novel esters of non steroidal anti-inflammatory drugs, α-lipoic acid and indol-3-acetic acid with cinnamyl alcohol were synthesised by a straightforward method and at high yields (60-98%). They reduced acute inflammation more than the parent acids and are potent inhibitors of soybean lipoxygenase. Selected structures decreased plasma lipidemic indices in Triton-induced hyperlipidemia to rats. Therefore, the synthesised compounds may add to the current knowledge about agents acting against various inflammatory disorders.

Harnessing Enzymatic Promiscuity in Myxochelin Biosynthesis for the Production of 5‐Lipoxygenase Inhibitors

The siderophore myxochelin A is a potent inhibitor of human 5-lipoxygenase (5-LO). To clarify whether the iron-chelating properties of myxochelin A are responsible for this activity, several analogues of this compound were generated in the native producer Pyxidicoccus fallax by precursor-directed biosynthesis. Testing in a cell-free assay unveiled three derivatives with bioactivity comparable with that of myxochelin A. Furthermore, it became evident that inhibition of 5-LO by myxochelins does not correlate with their iron affinities.

Studies on Anti-Inflammatory Action of Tryptanthrin, Using a Model of DSS-Induced Colitis of Mice and Magnetic Resonance Imaging

The action of tryptanthrin, a known natural alkaloid, a potent inhibitor of cyclooxygenase COX-2 and 5-lipoxygenase, was studied in a model of dextran sodium sulfate (DSS)-induced mouse colitis by magnetic resonance imaging (MRI). It was shown that the intra-ventricular treatment with tryptanthrin suspensions or emulsion at a dose of 25 mg/kg effectively diminishes lethality at experimental groups and normalizes morphometric parameters of intestine in the treated animals. MR imaging confirmed anti-inflammatory effect of this alkaloid and its capability to decrease the size of bowel walls in animals with colitis.

Synthesis, characterization, lipoxygenase inhibitory activity and in silico molecular docking of biaryl bis(benzenesulfonamide) and indol-3-yl-hydrazide derivatives

In this paper, we have screened a library of two different series of compounds to identify potent lipoxygenase (LOX) inhibitors. A number of new biphenyl bis(benzenesulfonamides) 2–3, indol-3-yl-benzenesulfonyl and acetohydrazides 4–5 and indol-3-yl-hydrazinecarboxylate 6 were synthesized and evaluated in vitro for LOX inhibitory activity. Compounds biphenyl bis(benzenesulfonamide) 2a and indol-3-yl-benzenesulfonylhydrazide 4e presented the best anti-LOX activity within these series with IC50 values 96.31 ± 0.18 and 81.21 ± 2.14 μM, respectively. The results were confirmed with docking studies.

Structural modifications of coumarin derivatives: Determination of antioxidant and lipoxygenase (LOX) inhibitory activity

In the present project, a series of coumarin analogues, were synthesised and evaluated for their antioxidant and soybean lipoxygenase inhibitory activity. A variety of structural modifications on the coumarin scaffold revealed interesting structure–activity relationships concerning the different biological assays. Prenyloxy-coumarins 9 and 10 displayed the best combined inhibition of lipid peroxidation and soybean lipoxygenase. Thiocoumarins 11 and 14 were identified as potent lipoxygenase inhibitors whereas hydrazone analogues 15 and 16 were efficient DPPH radical scavengers.

Effect of Dietary Stilbenes on 5-Lipoxygenase and Cyclooxygenases Activities In Vitro

Stilbenes contained in various foods are associated with health beneficial effects. In this study six natural and one synthetic stilbene were tested for their potential to regulate the activity of lipoxygenase and cyclooxygenase in vitro. The most potent inhibitor of 5-lipoxygenase was pterostilbene (IC50 = 9.32 μM), whereas the strongest inhibitor of cyclooxygenase-1 and cyclooxygenase-2 was pinostilbene (IC50s = 1.90 and 0.35 μM, respectively). Pterostilbene (IC50s = 11.70 and 27.04 μM for cyclooxygenase-1 and cyclooxygenase-2, respectively) and oxyresveratrol (IC50s = 18.49; 2.79 and 14.71 μM for 5-lipoxygenase, cyclooxygenase-1, and cyclooxygenase-2, respectively) were capable to inhibit catalytic activity of all three tested enzymes. Isorhapontigenin (IC50s = 8.81 and 24.00 μM for cyclooxygenase-1 and cyclooxygenase-2, respectively) and rhapontigenin (IC50s = 24.55 and 36.12 μM for cyclooxygenase-1 and cyclooxygenase-2, respectively) were only moderate or weak inhibitors of both cyclooxygenase forms. In summary, these results indicated that besides the known cyclooxygenase inhibitor resveratrol also other natural stilbenes could be potent inhibitors of the arachidonic acid pathway and deserve further attention as compounds with promising health benefits.

IN SILICO ANALYSIS OF FUNCTIONAL SNPS OF ALOX12 GENE AND IDENTIFICATION OF PHARMACOLOGICALLY SIGNIFICANT FLAVONOIDS AS LIPOXYGENASE INHIBITORS

Cancer is a disease affecting any part of the body and in comparison with normal cells there is an elevated level of lipoxygenase enzyme in different cancer cells. Thus generation of lipoxygenase enzyme inhibitors have suggested being valuable. Individual variation was identified by the functional effects of Single Nucleotide Polymorphisms (SNPs). 696 SNPs were identified from the ALOX12 gene, out of which 73 were in the coding non-synonymous region, from which 8 were found to be damaging. In silico analysis was performed to determine naturally occurring flavonoids such as isoflavones having the basic 3phenylchromen-4-one skeleton for the pharmacological activity, like Genistein, Diadzein, Irilone, Orobol and Pseudobaptigenin. O-methylated isoflavones such as Biochanin, Calycosin, Formononetin, Glycitein, Irigenin, 5-O-Methylgenistein, Pratensein, Prunetin, ψ-Tectorigenin, Retusin and Tectorigenine were also used for the study. Other natural products like Aesculetin, a coumarin derivative; flavones such as ajoene and baicalein were also used for the comparative study of these natural compounds along with acteoside and nordihydroguaiaretic acid (antioxidants) and active inhibitors like Diethylcarbamazine, Zileuton and Azelastine as standard for the computational analysis. The protein-ligand interaction was studied and the docking analysis was performed by Patch Dock server using the 3D3L human arachidonate 12-lipoxygenase protein. Out of the 19 herbal constituents selected, it was found that Diadzein, Biochanin, Glycitein, Irigenin, 5-O-Methylgenistein, ψ-Tectorigenin and Tectorigenin showed significant binding affinity in inhibiting lipooxygenase enzyme as compared with standard compounds of acteoside, nordihydroguaiaretic acid, Diethylcarbamazine, Zileuton and azelastine. Naturally occurring compounds on further advancement could act as potent lipoxygenase inhibitors.

SAR studies on curcumin's pro-inflammatory targets: discovery of prenylated pyrazolocurcuminoids as potent and selective novel inhibitors of 5-lipoxygenase.

The anticarcinogenic and anti-inflammatory properties of curcumin have been extensively investigated, identifying prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), key enzymes linking inflammation with cancer, as high affinity targets. A comparative structure-activity study revealed three modifications dissecting mPGES-1/5-LO inhibition, namely (i) truncation of the acidic, enolized dicarbonyl moiety and/or replacement by pyrazole, (ii) hydrogenation of the interaryl linker, and (iii) (dihydro)prenylation. The prenylated pyrazole analogue 11 selectively inhibited 5-LO, outperforming curcumin by a factor of up to 50, and impaired zymosan-induced mouse peritonitis along with reduced 5-LO product levels. Other pro-inflammatory targets of curcumin (i.e., mPGES-1, cyclooxygenases, 12/15-LOs, nuclear factor-κB, nuclear factor-erythroid 2-related factor-2, and signal transducer and activator of transcription 3) were hardly affected by 11. The strict structural requirements for mPGES-1 and 5-LO inhibition strongly suggest that specific interactions rather than redox or membrane effects underlie the inhibition of mPGES-1 and 5-LO by curcumin.

Virtual screening using the ligand ZINC database for novel lipoxygenase-3 inhibitors

The leukotrienes constitute a group of arachidonic acid-derived compounds with biologic activities suggesting important roles in inflammation and immediate hypersensitivity. Epidermis-type lipoxygenase-3 (ALOXE3), a distinct subclass within the multigene family of mammalian lipoxygenases, is a novel isoenzyme involved in the metabolism of leukotrienes and plays a very important role in skin barrier functions. Lipoxygenase selective inhibitors such as azelastine and zileuton are currently used to reduce inflammatory response. Nausea, pharyngolaryngeal pain, headache, nasal burning and somnolence are the most frequently reported adverse effects of these drugs. Therefore, there is still a need to develop more potent lipoxygenase inhibitors. In this paper, we report the screening of various compounds from the ZINC database (contains over 21 million compounds) using the Molegro Virtual Docker software against the ALOXE3 protein. Screening was performed using molecular constraints tool to filter compounds with physico-chemical properties similar to the 1N8Q bound ligand protocatechuic acid. The analysis resulted in 4319 Lipinski compliant hits which are docked and scored to identify structurally novel ligands that make similar interactions to those of known ligands or may have different interactions with other parts of the binding site. Our screening approach identified four molecules ZINC84299674; ZINC76643455; ZINC84299122 & ZINC75626957 with MolDock score of -128.901, -120.22, -116.873 & - 102.116 kcal/mol, respectively. Their energy scores were better than the 1N8Q bound co-crystallized ligand protocatechuic acid (with MolDock score of -77.225 kcal/mol). All the ligands were docked within the binding pocket forming interactions with amino acid residues.

Modulation of 5-Lipoxygenase in Proteotoxicity and Alzheimer's Disease

The accumulation of intracellular β amyloid (Aβ) may be one of the factors leading to neuronal cell death in Alzheimer's disease (AD). Using a pyrazole called CNB-001, which was selected for its ability to reduce intracellular Aβ, we show that the activation of the eIF2α/ATF4 arm of the unfolded protein response is sufficient to degrade aggregated intracellular Aβ. CNB-001 is a potent inhibitor of 5-lipoxygenase (5-LOX), decreases 5-LOX expression, and increases proteasome activity. 5-LOX inhibition induces eIF2α and PERK (protein kinase R-like extracellular signal-regulated kinase) phosphorylation, and HSP90 and ATF4 levels. When fed to AD transgenic mice, CNB-001 also increases eIF2α phosphorylation and HSP90 and ATF4 levels, and limits the accumulation of soluble Aβ and ubiquitinated aggregated proteins. Finally, CNB-001 maintains the expression of synapse-associated proteins and improves memory. Therefore, 5-LOX metabolism is a key element in the promotion of endoplasmic reticulum dysfunction, and its inhibition under conditions of stress is sufficient to reduce proteotoxicity both in vivo and in vitro.

Molecular modeling and pharmacophore approach for structural requirements of some 2-substituted-1-naphthols derivatives as potent 5-lipoxygenase inhibitors

Molecular modeling and pharmacophore study has been performed on a series of 2-Substituted-1-naphthols derivatives with potent 5-lipoxygenase inhibitory activity. Structural features responsible for the activity of the compounds were characterized by using physicochemical, topological, and electrotopological descriptors, calculated from the Molecular Design Suite Software (V-life MDS™ 3.5). The relationship developed between biological activity and electrostatic, steric, hydrophobicity parameters was explored to generate combinatorial library with various substitution. This library can be explored for the synthesis and study of future potential anti-inflammatory agent. The requirements for the 5-lipoxygenase inhibitory activity are explored with 2D-QSAR, group based QSAR (G-QSAR), and k-nearest neighbour studies. The statistically significant 2D-QSAR model having r 2 = 0.8502 and q 2 = 0.8144 with pred_r 2 = 0.8072 and the best group based QSAR (G-QSAR) model having r 2 = 0.9137 and q 2 = 0.7808 with pred_r 2 = 0.8490 was developed by simulated annealing based partial least squares method. Further analysis using k-nearest neighbour 3D-QSAR technique identifies two models obtained by simulated annealing (SA) and genetic algorithm (GA)-based partial least squares methods leading to 5-lipoxygenase activity prediction. The best simulated annealing QSAR model showed q 2 = 0.8547, r 2 = 0.8963, and standard error = 0.3677. It was observed that steric properties predicted by k-nearest neighbour MFA contours can be related to 5-lipoxygenase activity. The predictive ability of the resultant model was evaluated using a test set molecules and the predicted r 2 = 0.8162. The best pharmacophore model with hydrophobic, hydrogen bond donor (HBD), and aromatic features has root mean square deviation (RMSD) of 0.5746. The QSAR model suggests that electron-withdrawing character is favorable for the 5-lipoxygenase inhibitory activity. This suggests that electron-withdrawing groups like a chlorine or fluorine atoms at naphthol moiety are good for anti-inflammatory activity. In addition to the electron-withdrawing character, electron-donating groups, hydrophobic and hydrogen bond donor groups positively contribute to the 5-lipoxygenase inhibition. The results of 2D-QSAR, Group based QSAR, and k-nearest neighbour 3D-QSAR studies give detailed structural insights as well as highlights important binding features of these 2-Substituted-1-naphthols derivatives as anti-inflammatory agents which can provide guidance for the rational design of novel potent 5-lipoxygenase inhibitors.

Abstract 9954: 5-Lipoxygenase Inhibitor VIA-2291 (Atreleuton) Intake Improves Left Ventricular Ejection Fraction in Patients with Recent Acute Coronary Syndrome

Background: Previous studies have shown coronary artery syndrome can result in left ventricular myocardial remodeling (LVMR); and progressive LVMR after infarction could lead to decline in ejection fraction. In this study we evaluated the effect of a potent and selective 5-Lipoxygenase inhibitor, VIA-2291, on Left Ventricular Ejection Fraction (LVEF) in patients with recent Acute Coronary Syndrome (ACS) on top of standard medical therapy. Methods: This is a double blinded: placebo controlled: dose ranging: randomized: multicenter trial (clinicaltrials.gov NCT00358826 ) of 56 individuals with recent ACS who were recruited and followed for 24 weeks in an imaging substudy. Subjects were randomized to four study arms including: 25 mg, 50 mg, and 100 mg of VIA-2291 as well as placebo. LVEF and Stroke Volume (SV) were measured post-hoc by contrast enhanced Cardiac Computed Tomographic Angiography on GE Advantage Windows 4.4 Workstations (GE Healthcare, Milwaukee, WI). Result: There were no major differences between traditional cardiovascular risk factors among the 4 randomized study arms. LVEF improved dramatically in subjects who had taken VIA-2291 vs. placebo: 1.8±8.4 vs. -3.0±9.3 (p=0.0001). Similarly SV improved significantly with VIA-2291 vs. placebo: 3.9±15.9 vs. -4.8±17.2 (p=0.0001). VIA-2291 demonstrated a dose dependent effect on LVEF and SV with largest benefit achieved with the highest dose of the drug (100mg) vs. Placebo; LVEF and SV: 2.64±6.06 and 4.65±14.01, p=0.0001, respectively (Figure 1). Of note, the placebo group was shown to have a decrease in LVEF and SV -3.1±9.3 and -4.8±17.2, respectively, which can be attributed to post-ACS myocardial-remodeling. Conclusion: The addition of VIA-2291 to standard of care medical regimen is able to improve ejection fraction dramatically in patient with recent coronary artery syndrome over a 6 month follow-up period. Benefits of VIA-2291 are dose dependent.