Synthesis, Bioactivity, Pharmacokinetic and Biomimetic Properties of Multi-Substituted Coumarin Derivatives.

A series of novel multi-substituted coumarin derivatives were synthesized, spectroscopically characterized, and evaluated for their antioxidant activity, soybean lipoxygenase (LOX) inhibitory ability, their influence on cell viability in immortalized human keratinocytes (HaCaT), and cytotoxicity in adenocarcinomic human alveolar basal epithelial cells (A549) and human melanoma (A375) cells, in vitro. Coumarin analogues 4a-4f, bearing a hydroxyl group at position 5 of the coumarin scaffold and halogen substituents at the 3-phenyl ring, were the most promising ABTS•+ scavengers. 6,8-Dibromo-3-(4-hydroxyphenyl)-4-methyl-chromen-2-one (4k) and 6-bromo-3-(4,5-diacetyloxyphenyl)-4-methyl-chromen-2-one (3m) exhibited significant lipid peroxidation inhibitory activity (IC50 36.9 and 37.1 µM). In the DCF-DA assay, the 4'-fluoro-substituted compound 3f (100%), and the 6-bromo substituted compounds 3i (80.9%) and 4i (100%) presented the highest activity. The 3'-fluoro-substituted coumarins 3e and 4e, along with 3-(4-acetyloxyphenyl)-6,8-dibromo-4-methyl-chromen-2-one (3k), were the most potent lipoxygenase (LOX) inhibitors (IC50 11.4, 4.1, and 8.7 µM, respectively) while displaying remarkable hydroxyl radical scavenging ability, 85.2%, 100%, and 92.9%, respectively. In silico docking studies of compounds 4e and 3k, revealed that they present allosteric interactions with the enzyme. The majority of the analogues (100 µΜ) did not affect the cell viability of HaCaT cells, though several compounds presented over 60% cytotoxicity in A549 or A375 cells. Finally, the human oral absorption (%HOA) and plasma protein binding (%PPB) properties of the synthesized coumarins were also estimated using biomimetic chromatography, and all compounds presented high %HOA (>99%) and %PPB (60-97%) values.

Antioxidant Serine-(NSAID) Hybrids with Anti-Inflammatory and Hypolipidemic Potency.

A series of L-serine amides of antioxidant acids, such as Trolox, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (phenolic derivative of cinnamic acid) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (structurally similar to butylated hydroxytoluene), was synthesized. The hydroxy group of serine was esterified with two classical NSAIDs, ibuprofen and ketoprofen. The Trolox derivatives with ibuprofen (7) and ketoprofen (10) were the most potent inhibitors of lipid peroxidation (IC50 3.4 µΜ and 2.8 µΜ), several times more potent than the reference Trolox (IC50 25 µΜ). Most of the compounds decreased carrageenan-induced rat paw edema (37-67% at 150 µmol/kg). They were moderate inhibitors of soybean lipoxygenase, with the exception of ibuprofen derivative 8 (IC50 13 µΜ). The most active anti-inflammatory compounds exhibited a significant decrease in lipidemic indices in the plasma of Triton-induced hyperlipidemic rats, e.g., the most active compound 9 decreased triglycerides, total cholesterol and low-density lipoprotein cholesterol by 52%, 61% and 70%, respectively, at 150 µmol/kg (i.p.), similar to that of simvastatin, a well-known hypocholesterolemic drug. Since the designed compounds seem to exhibit multiple pharmacological actions, they may be of use for the development of agents against inflammatory and degenerative conditions.

Probing phenylcarbamoylazinane-1,2,4-triazole amides derivatives as lipoxygenase inhibitors along with cytotoxic, ADME and molecular docking studies.

Hunting small molecules as anti-inflammatory agents/drugs is an expanding and successful approach to treat several inflammatory diseases such as cancer, asthma, arthritis, and psoriasis. Besides other methods, inflammatory diseases can be treated by lipoxygenase inhibitors, which have a profound influence on the development and progression of inflammation. In the present study, a series of new N-alkyl/aralky/aryl derivatives (7a-o) of 2-(4-phenyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide was synthesized and screened for their inhibitory potential against the enzyme 15-lipoxygenase. The simple precursor ethyl piperidine-4-carboxylate (a) was successively converted into phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and N-phenylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4), then in combination with electrophiles (6a-o) through further multistep synthesis, final products (7a-o) were generated. All the synthesized compounds were characterized by FTIR, 1H, 13C NMR spectroscopy, EIMS, and HREIMS spectrometry. Almost all the synthesized compounds showed excellent inhibitory potential against the tested enzyme. Compounds 7c, 7f, 7d, and 7g displayed potent inhibitory potential (IC50 9.25 ± 0.26 to 21.82 ± 0.35 µM), followed by the compounds 7n, 7h, 7e, 7a, 7b, 7l, and 7o with IC50 values in the range of 24.56 ± 0.45 to 46.91 ± 0.57 µM. Compounds 7c, 7f, 7d exhibited 71.5 to 83.5% cellular viability by MTT assay compared with standard curcumin (76.9%) when assayed at 0.125 mM concentration. In silico ADME studies supported the drug-likeness of most of the molecules. In vitro inhibition studies were substantiated by molecular docking wherein the phenyl group attached to the triazole ring was making a π-δ interaction with Leu607. This work reveals the possibility of a synthetic approach of compounds in relation to lipoxygenase inhibition as potential lead compounds in drug discovery.

Structural considerations on lipoxygenase function, inhibition and crosstalk with nitric oxide pathways.

Lipoxygenases (LOX) are non-heme iron-containing enzymes that catalyze regio- and stereo-selective dioxygenation of polyunsaturated fatty acids (PUFA). Mammalian LOXs participate in the eicosanoid cascade during the inflammatory response, using preferentially arachidonic acid (AA) as substrate, for the synthesis of leukotrienes (LT) and other oxidized-lipid intermediaries. This review focus on lipoxygenases (LOX) structural and kinetic implications on both catalysis selectivity, as well as the basic and clinical implications of inhibition and interactions with nitric oxide (•NO) and nitroalkenes pathways. During inflammation •NO levels are increasingly favoring the formation of reactive nitrogen species (RNS). •NO may act itself as an inhibitor of LOX-mediated lipid oxidation by reacting with lipid peroxyl radicals. Besides, •NO may act as an O2 competitor in the LOX active site, thus displaying a protective role on lipid-peroxidation. Moreover, RNS such as nitrogen dioxide (•NO2) may react with lipid-derived species formed during LOX reaction, yielding nitroalkenes (NO2FA). NO2FA represents electrophilic compounds that could exert anti-inflammatory actions through the interaction with critical LOX nucleophilic amino acids. We will discuss how nitro-oxidative conditions may limit the availability of common LOX substrates, favoring alternative routes of PUFA metabolization to anti-inflammatory or pro-resolutive pathways.

4-(4-Chlorophenyl)thiazol-2-amines as pioneers of potential neurodegenerative therapeutics with anti-inflammatory properties based on dual DNase I and 5-LO inhibition.

Eleven new 4-(4-chlorophenyl)thiazol-2-amines were synthesized and, together with nine known derivatives, evaluated in vitro for inhibitory properties towards bovine pancreatic DNase I. Three compounds (18-20) inhibited DNase I with IC50 values below 100 µM, with compound 19 being the most potent (IC50 = 79.79 µM). Crystal violet, used as a positive control in the absence of a "golden standard", exhibited almost 5-fold weaker DNase I inhibition. Pharma/E-State RQSAR models clarified critical structural fragments relevant for DNase I inhibition. Molecular docking and molecular dynamics simulation defined the 4-(4-chlorophenyl)thiazol-2-amines interactions with the most important catalytic residues of DNase I. Ligand-based pharmacophore modeling and virtual screening confirmed the chemical features of 4-(4-chlorophenyl)thiazol-2-amines required for DNase I inhibition and proved the absence of structurally similar molecules in available databases. Compounds 18-20 have been shown as very potent 5-LO inhibitors with nanomolar IC50 values obtained in cell-free assay, with compound 20 being the most potent (IC50 = 50 nM). Molecular docking and molecular dynamics simulations into the binding site of 5-LO enzyme allowed us to clarify the binding mode of these dual DNase I/5-LO inhibitors. It was shown that compounds 18-20 uniquely show interactions with histidine residues in the catalytic site of DNase I and 5-LO enzyme. In the absence of potent organic DNase I inhibitors, compounds 18-20 represent a good starting point for the development of novel Alzheimer's therapeutics based on dual 5-LO and DNase I inhibition, which also have anti-inflammatory properties.

Design, Synthesis and Biological Screening of Novel 1,5-Diphenyl-3-(4-(trifluoromethyl)phenyl)-2-pyrazoline Derivatives.

1-Phenyl-5-substituted-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole derivatives were synthesized from chalcone derivatives. The structures of compounds were characterized by IR, 1H NMR spectroscopic methods and elemental analysis. All compounds were evaluated for their in vitro antioxidant activity using DPPH and ABTS methods, anti-inflammatory activity using lipoxygenase inhibitory method and antidiabetic activity using the ?-glucosidase inhibitory method. Especially, pyrazoline derivatives exhibited stronger anti-inflammatory activity than the reference drug indomethacin (IC50: 50.45 µM) and their IC50 values were in the range of 0.68 and 4.45 µM. In addition, the ADME properties of all chalcone and pyrazoline derivatives were calculated by Lipinski's and Veber's rules.

Design, synthesis and identification of novel coumaperine derivatives for inhibition of human 5-LOX: Antioxidant, pseudoperoxidase and docking studies.

5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition. CP-209, a catechol type dihydroxyl derivative and CP-262-F2, a vicinal trihydroxyl derivative exhibited, 82.7% and 82.5% inhibition of 5-LOX respectively at 20 µM. Their IC50 values are 2.1 ±â€¯0.2 µM and 2.3 ±â€¯0.2 µM respectively, and are comparable to zileuton, IC50 = 1.4 ±â€¯0.2 µM. CP-155, a methylenedioxy derivative (a natural product) and CP-194, a 2,4,6-trimethoxy derivative showed 76.0% and 77.1% inhibition of 5-LOX respectively at 20 µM. Antioxidant study revealed that CP-209 and 262-F2 (at 20 µM) scavenged DPPH radical by 76.8% and 71.3% respectively. On the other hand, CP-155 and 194 showed very poor DPPH radical scavenging activity. Pseudo peroxidase assay confirmed that the mode of action of CP-209 and 262-F2 were by redox process, similar to zileuton, affecting the oxidation state of the metal ion in the enzyme. On the contrary, CP-155 and 194 probably act through some other mechanism which does not involve the disruption of the oxidation state of the metal in the enzyme. Molecular docking of CP-155 and 194 to the active site of 5-LOX and binding energy calculation suggested that they are non-competitive inhibitors. The In-Silico ADME/TOX analysis shows the active compounds (CP-155, 194, 209 and 262-F2) are with good drug likeliness and reduced toxicity compared to existing drug. These studies indicate that there is a great potential for coumaperine derivatives to be developed as anti-inflammatory drug.

CNB-001, a pleiotropic drug is efficacious in embolized agyrencephalic New Zealand white rabbits and ischemic gyrencephalic cynomolgus monkeys.

Ischemic stroke is an acute neurodegenerative disease that is extremely devastating to patients, their families and society. Stroke is inadequately treated even with endovascular procedures and reperfusion therapy. Using an extensive translational screening process, we have developed a pleiotropic cytoprotective agent with the potential to positively impact a large population of brain ischemia patients and revolutionize the process used for the development of new drugs to treat complex brain disorders. In this unique translational study article, we document that the novel curcumin-based compound, CNB-001, when administered as a single intravenous dose, has significant efficacy to attenuate clinically relevant behavioral deficits following ischemic events in agyrencephalic rabbits when administered 1 h post-embolization and reduces infarct growth in gyrencephalic non-human primates, when administered 5 min after initiation of middle cerebral artery occlusion. CNB-001 is safe and does not increase morbidity or mortality in either research species. Mechanistically, CNB-001 inhibits human 5- and 15-lipoxygenase in vitro, and can attenuate ischemia-induced inflammatory markers, and oxidative stress markers, while potentially promoting synaptic plasticity mediated by enhanced brain-derived neurotrophic factor (BDNF).

Characterization of the molecular mechanism of 5-lipoxygenase inhibition by 2-aminothiazoles.

5-Lipoxygenase (5-LO, EC1.13.11.34) has been implicated in the pathogenesis of inflammatory and immune diseases. Recently, aminothiazole comprising inhibitors have been discovered for this valuable target. Yet, the molecular mode of action of this class of substances is only poorly understood. Here, we present the detailed molecular mechanism of action of the compound class and the in vitro pharmacological profile of two lead compounds ST-1853 and ST-1906. Mechanistic studies with recombinant proteins as well as intact cell assays enabled us to define this class as a novel type of 5-LO inhibitors with unique characteristics. The parent compounds herein presented a certain reactivity concerning oxidation and thiol binding: Unsubstituted aminophenols bound covalently to C159 and C418 of human 5-LO. Yet, dimethyl substitution of the aminophenol prevented this reactivity and slowed down phase II metabolism. Both ST-1853 and ST-1906 confirmed their lead likeness by retaining their high potency in physiologically relevant 5-LO activity assays, high metabolic stability, high specificity and non-cytotoxicity.

New sterols with anti-inflammatory potentials against cyclooxygenase-2 and 5-lipoxygenase from Paphia malabarica.

Marine bivalves occupy a leading share in the total edible molluscs at the coastline regions of south-eastern Asia, and are found to possess significant nutritional and biological potential. Various in vitro evaluation (antioxidant and anti-inflammatory) guided purification of ethyl acetate-methanol (EtOAc-MeOH) extract of bivalve clam, Paphia malabarica characterised two new sterol derivatives as 23-gem-dimethylcholesta-5-en-3ß-ol (1) and (22E)-241,242-methyldihomocholest-5,22-dien-3ß-ol (2) collected from the south-west coast of Arabian Sea. Their structures were unambiguously assigned on the basis of 1D, 2D NMR spectroscopy and mass spectrometry. The antioxidant and anti-inflammatory activities of 2 as determined by DPPH/ABTS+ radical scavenging and anti-cyclooxygenase-2/5-lipoxygenase assays were significantly greater (IC50 < 1 mg/mL) than 1 (IC50 > 1 mg/mL). Structure-activity relationship analysis revealed that the bioactivities of these compounds were directly proportional to the electronic and lipophilic parameters. This is the first report of the occurrence and characterisation of 23-gem-dimethyl-3ß-hydroxy-Δ5-cholestane nucleus and C-30 dihomosterol from marine organisms.

Gastrointestinal Motility Variation and Implications for Plasma Level Variation: Oral Drug Products.

The oral route of administration is still by far the most ubiquitous method of drug delivery. Development in this area still faces many challenges due to the complexity and inhomogeneity of the gastrointestinal environment. In particular, dosing unpredictably relative to motility phase means the gastrointestinal environment is a random variable within a defined range. Here, we present a mass balance analysis that captures this variation and highlights the effects of gastrointestinal motility, exploring what impacts it ultimately has on plasma levels and the relationship to bioequivalence for high solubility products with both high and low permeability (BCS I and III). Motility-dependent compartmental absorption and transit (MDCAT) mechanistic analysis is developed to describe the underlying fasted state cyclical motility and how the contents of the gastrointestinal tract are propelled.

Aminothiazole-featured pirinixic acid derivatives as dual 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 inhibitors with improved potency and efficiency in vivo.

Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2-aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.4 µM, respectively) and bioactivity in vivo. Computational analysis presumes binding sites of 16 at the tip of the 5-LO catalytic domain and within a subpocket of the mPGES-1 active site. Compound 16 (10 µM) hardly suppressed cyclooxygenase (COX)-1/2 activities, failed to inhibit 12/15-LOs, and is devoid of radical scavenger properties. Finally, compound 16 reduced vascular permeability and inflammatory cell infiltration in a zymosan-induced mouse peritonitis model accompanied by impaired levels of cysteinyl-leukotrienes and prostaglandin E2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs.

Myrtucommulone from Myrtus communis: metabolism, permeability, and systemic exposure in rats.

Nonsteroidal anti-inflammatory drug intake is associated with a high prevalence of gastrointestinal side effects, and severe cardiovascular adverse reactions challenged the initial enthusiasm in cyclooxygenase-2 inhibitors. Recently, it was shown that myrtucommulone, the active ingredient of the Mediterranean shrub Myrtus communis, dually and potently inhibits microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase, suggesting a substantial anti-inflammatory potential. However, one of the most important prerequisites for the anti-inflammatory effects in vivo is sufficient bioavailability of myrtucommulone. Therefore, the present study was aimed to determine the permeability and metabolic stability in vitro as well as the systemic exposure of myrtucommulone in rats. Permeation studies in the Caco-2 model revealed apparent permeability coefficient values of 35.9 ·â€Š10⁻6 cm/s at 37 °C in the apical to basolateral direction, indicating a high absorption of myrtucommulone. In a pilot rat study, average plasma levels of 258.67 ng/mL were reached 1 h after oral administration of 4 mg/kg myrtucommulone. We found that myrtucommulone undergoes extensive phase I metabolism in human and rat liver microsomes, yielding hydroxylated and bihydroxylated as well as demethylated metabolites. Physiologically-based pharmacokinetic modeling of myrtucommulone in the rat revealed rapid and extensive distribution of myrtucommulone in target tissues including plasma, skin, muscle, and brain. As the development of selective microsomal prostaglandin E2 synthase-1 inhibitors represents an interesting alternative strategy to traditional nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for the treatment of chronic inflammation, the present study encourages further detailed pharmacokinetic investigations on myrtucommulone.

Pharmacokinetic, distribution, metabolism, and excretion of (Z)-2-amino-1,5-dihydro-1-methyl-5-[4-(mesyl)benzylidene]-4H-imidazol-4-one mesilate (ZLJ-601) in Sprague-Dawley rats.

(Z)-2-amino-1,5-dihydro-1-methyl-5-[4-(mesyl)benzylidene]-4H-imidazol-4-one mesilate (ZLJ-601) is an imidazolone COX/5-LOX inhibitor, which has excellent anti-inflammatory activity with an improved gastrointestinal safety profile. The purpose of this study was to evaluate the in vivo absorption, distribution, metabolism, and excretion of ZLJ-601 in Sprague-Dawley rats. After intravenous or intragastric administration to rats, the concentration of ZLJ-601 in plasma, bile, urine, feces and various types of tissues was detected by LC-MS. We also conducted the identification of metabolites using tandem mass spectrometry. After the intravenous administration, the t(1/2) ranged from 38.71 to 42.62 min and the AUC increased in a dose-proportional manner. After oral dosing, the plasma level of ZLJ-601 peaked at 28.33 min, having a C(max) value of 0.26 mg/l, and the bioavailability was only 4.92%. The highest tissue concentration of ZLJ-601 was observed in lung and kidney, but it was not found in brain. The majority of unchanged ZLJ-601 was excreted in urine (∼35.87%) within 36 h. Two main metabolites are the hydroxylation product and the glucuronide conjugate of the hydroxylation product.

Discovery of potent and selective inhibitors of human platelet-type 12- lipoxygenase.

We report the discovery of novel small molecule inhibitors of platelet-type 12-human lipoxygenase, which display nanomolar activity against the purified enzyme, using a quantitative high-throughput screen (qHTS) on a library of 153607 compounds. These compounds also exhibit excellent specificity, >50-fold selectivity vs the paralogues, 5-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity vs ovine cyclooxygenase-1 and human cyclooxygenase-2. Kinetic experiments indicate this chemotype is a noncompetitive inhibitor that does not reduce the active site iron. Moreover, chiral HPLC separation of two of the racemic lead molecules revealed a strong preference for the (-)-enantiomers (IC(50) of 0.43 ± 0.04 and 0.38 ± 0.05 µM) compared to the (+)-enantiomers (IC(50) of >25 µM for both), indicating a fine degree of selectivity in the active site due to chiral geometry. In addition, these compounds demonstrate efficacy in cellular models, which underscores their relevance to disease modification.

Cellular and molecular mechanisms of anti-inflammatory effect of Aflapin: a novel Boswellia serrata extract.

There is significant number of evidences suggesting the anti-inflammatory properties of gum resin extracts of Boswellia serrata containing 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) and their promising potential as therapeutic interventions against inflammatory diseases such as osteoarthritis (OA). Unfortunately, the poor bioavailability of AKBA following oral administration might limit the anti-inflammatory efficacy of standardized Boswellia extract(s). To address this issue, we describe a novel composition called Aflapin, which contains B. serrata extract enriched in AKBA and non-volatile oil portion of B. serrata gum resin. Our observations show that the availability of AKBA in systemic circulation of experimental animals is increased by 51.78% in Aflapin-supplemented animals, in comparison with that of 30% AKBA standardized extract or BE-30 (5-Loxin(®)). Consistently, Aflapin confers better anti-inflammatory efficacy in Freund's Complete Adjuvant (FCA)-induced inflammation model of Sprague-Dawley rats. Interestingly, in comparison with BE-30, Aflapin(®) also provides significantly better protection from IL-1ß-induced death of human primary chondrocytes and improves glycosaminoglycans production in human chondrocytes. In Tumor necrosis factor alpha (TNFα)-induced human synovial cells, the inhibitory potential of Aflapin (IC(50) 44.736 ng/ml) on matrix metalloproteinase-3 (MMP-3) production is 14.83% better than that of BE-30 (IC(50) 52.528 ng/ml). In summary, our observations collectively suggest that both the Boswellia products, BE-30 (5-Loxin(®)) and Aflapin, exhibit powerful anti-inflammatory efficacy and anti-arthritic potential. In particular, in comparison with BE-30, Aflapin provides more potential benefits in recovering articular cartilage damage or protection from proteolytic degradation due to inflammatory insult in arthritis such as osteoarthritis or rheumatoid arthritis.

Discovery of (2-fluoro-benzyl)-(2-methyl-2-phenethyl-2H-chromen-6-yl)-amine (KRH-102140) as an orally active 5-lipoxygenase inhibitor with activity in murine inflammation models.

OBJECTIVE AND DESIGN: We investigated anti-inflammatory properties of a novel 5-lipoxygenase (5-LO) inhibitor, KRH-102140, in vitro and in vivo. 5-LO enzyme activity was assayed using insect cell lysates overexpressing rat 5-LO. The leukotriene B(4) (LTB(4)) level was assayed in rat basophilic leukemia (RBL-1) cell line. ICR (Institute of Cancer Research) mice were used for in vivo assays. Mouse ear edema was induced by topical application of arachidonic acid. An air pouch was induced by subcutaneous injection of sterile air into mice, followed by zymosan treatment. Sprague-Dawley rats were used for pharmacokinetic studies. RESULTS: KRH-102140 inhibited 5-LO activity with an IC(50) value of 160 ± 23 nmol/l in parallel with LTB(4) inhibition in RBL-1 cells. Oral administration of KRH-102140 (10-100 mg/kg) reduced ear edema, myeloperoxidase activity and LTB(4) production in murine inflammation models. Oral bioavailability as determined in rats was 66%. CONCLUSIONS: Our results show that KRH-102140, a new 5-LO inhibitor, exhibits potent anti-inflammatory activities in vitro as well as in vivo.

Potent and selective 5-LO inhibitor bearing benzothiophene pharmacophore: discovery of MK-5286.

The strategy and SAR studies that led to the discovery of a novel potent and orally available 5-lipoxygenase (5-LO) inhibitor 3-(4-fluorophenyl)-6-({4-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1-benzothiophene-2-carboxamide ((S)-2l or MK-5286) were described.

Pharmacology of PF-4191834, a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain.

5-Lipoxygenase (LOX) is an important arachidonic acid-metabolizing enzyme producing leukotrienes and other proinflammatory lipid mediators with potent pathophysiological functions in asthma and other inflammatory diseases. 4-(3-(4-(1-Methyl-1H-pyrazol-5-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide (PF-4191834) is a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain. In vitro and in vivo assays were developed for the evaluation of a novel 5-LOX inhibitor using conditions of maximal enzyme activity. PF-4191834 exhibits good potency in enzyme- and cell-based assays, as well as in a rat model of acute inflammation. Enzyme assay results indicate that PF-4191834 is a potent 5-LOX inhibitor, with an IC(50) = 229 +/- 20 nM. Furthermore, it demonstrated approximately 300-fold selectivity for 5-LOX over 12-LOX and 15-LOX and shows no activity toward the cyclooxygenase enzymes. In addition, PF-4191834 inhibits 5-LOX in human blood cells, with an IC(80) = 370 +/- 20 nM. This inhibitory concentration correlates well with plasma exposures needed for in vivo efficacy in inflammation in models of inflammatory pain. The combination of potency in cells and in vivo, together with a sustained in vivo effect, provides PF-4191834 with an overall pharmacodynamic improvement consistent with once a day dosing.

Evaluation of lipoxygenase inhibitory activity of anacardic acids.

6-Alkylsalicylic acids inhibit the linoleic acid peroxidation catalyzed by soybean lipoxygenase-1 (EC 1.13.11.12, type 1) competitively and without pro-oxidant effects. This activity is largely dependent on the nature of their alkyl side chains. Inhibitory activities of anacardic acids, viz. 6-pentadec(en)ylsalicylic acids, isolated from the cashew Anacardium occidentale, were initially used for comparison because their aromatic head portions are the same. Consequently, the data should be interpreted to mean that changes in the hydrophobic side chain tail portions of the molecules evaluated correlate with the specific activity determined.