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At least 19 recordsLinked to original sources
PubMed1986

Islet-activating protein inhibits leukotriene D4- and leukotriene C4- but not bradykinin- or calcium ionophore-induced prostacyclin synthesis in bovine endothelial cells.

Incubation of the bovine endothelial cell line, CPAE, with leukotriene D4, leukotriene C4, bradykinin, or the calcium ionophore A23187 results in the release of arachidonic acid metabolites including 6-keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin. Pretreatment of these cells with the pertussis toxin islet-activating protein (IAP) results in a dose-dependent inhibition of the release of arachidonic acid metabolites and prostacyclin in response to leukotriene D4 and leukotriene C4. In contrast, similar responses evoked by bradykinin or ionophore were not significantly altered by the IAP pretreatment of the cells. IAP in the presence of [32P]NAD specifically [32P]ADP-ribosylates a 41-kDa protein in membranes prepared from CPAE cells. Pretreatment of the intact cells with IAP resulted in a dose-dependent inhibition of subsequent 32P labeling of the toxin substrate in the membranes and correlates with the uncoupling of the leukotriene responses. These results suggest that the 41-kDa IAP substrate, presumably a guanine nucleotide regulatory protein, mediates the response of CPAE cells to leukotriene D4 and leukotriene C4, but not to bradykinin or the calcium ionophore.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Antagonism of leukotriene C4, leukotriene D4 and leukotriene E4 vasoconstrictor responses in the conscious rat with the peptidoleukotriene receptor antagonist SK&F 104353: evidence for leukotriene D4 receptor heterogeneity.

The purpose of these experiments was to investigate the effects of the selective peptidoleukotriene receptor antagonist, SK&F 104353, on leukotriene (LT)C4, LTD4 and LTE4 vasopressor responses in conscious, normotensive rats. Steady-state plasma concentrations of SK&F 104353 at infusion rates of 0.2 mg/kg + 1 mg/kg/hr, 1 mg/kg + 3 mg/kg/hr or 2 mg/kg + 10 mg/kg/hr were 0.5, 1.6 and 9.4 micrograms/ml, respectively, indicating that the plasma concentrations of SK&F 104353 were related directly to the infusion rate. LTC4, LTD4 and LTE4 (0.17-170 nmol/kg i.v.) produced dose-dependent increases in mean blood pressure. The ED20 dose (i.e., dose required to increase blood pressure 20 mm Hg) of LTC4, LTD4 or LTE4 was 2.7 +/- 0.4, 2.2 +/- 0.3 and 109 +/- 17 nmol/kg, respectively. SK&F 104353 produced dose-dependent, parallel shifts to the right in the LTC4 dose-response curve. Administration of SK&F 104353 at doses of 0.2 mg/kg + 1 mg/kg/hr, 1 mg/kg + 3 mg/kg/hr or 2 mg/kg + 10 mg/kg/hr produced dose ratios (i.e., ratio of ED20 in presence of SK&F 104353 to that of the vehicle group) of 6, 12 and 26, respectively. Against LTD4 responses, SK&F 104353 at doses of 0.1 mg/kg + 0.3 mg/kg/hr or 0.2 mg/kg + 1 mg/kg/hr produced dose ratios of 3 and 9, respectively. At a dose of 1 mg/kg + 3 mg/kg/hr, there was no further increase in the dose ratio, whereas a dose of 2 mg/kg + 10 mg/kg/hr resulted in a dose ratio of greater than 100.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Visualization and comparison of molecular dynamics simulations of leukotriene C4, leukotriene D4, and leukotriene E4.

Molecular dynamics simulations of leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4) were carried out, and the data were visualized in an animated video format. Three-dimensional ghost images show the positions of the heavy atoms of all three molecules throughout the simulations. The ghost images can be superimposed to give a single three-dimensional image in which the shapes of the most populated conformers of each molecule are apparent and can be compared. Leukotriene D4 was found to occupy mostly T-shaped conformations, while LTC4 occupied mostly cup-shaped conformations, and LTE4 occupied a wide range of conformations spanning the LTD4 and LTC4 types. Digital filtering and graphing of the internal geometries of the molecules as a function of time revealed differences in dynamic behavior. The results are discussed in light of current knowledge about leukotriene receptors.

Computer Graphics↗
PubMed1988

Leukotriene receptor antagonists. III. Pharmacological and chemical studies with LY137617, a leukotriene D4 and leukotriene E4 receptor antagonist.

A series of chlorophenoxyalkyl acids were prepared and evaluated as pharmacological antagonists of leukotriene D4. Structure-activity relationship studies pointed to LY137617 as a compound with possible therapeutic value. In experiments on isolated smooth muscles from the guinea-pig, this agent was a selective and moderately potent antagonist of leukotriene D4 and also leukotriene E4. Other in vitro experiments demonstrated that LY137617 had a high affinity for protein molecules. This was reflected in vivo as a weaker than expected efficacy against leukotriene-mediated events, limiting the compound's potential as a clinical candidate. Nevertheless, agents of this type will prove useful in the laboratory to increase knowledge of leukotriene receptor-antagonist interactions.

Animals↗
PubMed1987

Cilastatin-sensitive dehydropeptidase I enzymes from three sources all catalyze carbapenem hydrolysis and conversion of leukotriene D4 to leukotriene E4.

The dipeptidase, dehydropeptidase I (EC 3.4.13.11), was purified to homogeneity from rat lung, rat kidney, and hog kidney. Analysis of physical parameters (subunit molecular weights, Km values for glycyldehydrophenylalanine, Ki values for dehydropeptidase I inhibitors, and immunoreactivity) showed the rat dipeptidases to be similar to each other but different from the hog dipeptidase. However, all three enzymes hydrolyzed imipenem and converted leukotriene D4 to leukotriene E4, and these activities were inhibited by cilastatin.

Animals↗
PubMed1983

Conversion of leukotriene D4 to leukotriene E4 by a dipeptidase released from the specific granule of human polymorphonuclear leucocytes.

Leukotriene D4 (LTD4), the most active spasmogenic leukotriene constituent of the slow reacting substance of anaphylaxis was converted by suspended human polymorphonuclear leucocytes (PMNs) to a single, less polar metabolite which was not further catabolized. This product was identified as leukotriene E4 (LTE4) by its retention time during reverse phase-high performance liquid chromatography (RP-HPLC) and subsequent bioassay on the guinea-pig ileum. LTD4 with a retention time of 21 +/- 1.6 min (mean +/- SD) and a contractile activity of 5.0 +/- 0.4 u./pmol (mean +/- SD) was quantitatively converted extracellularly by PMNs to LTE4 with a retention time of 26 +/- 1.8 min and a contractile activity of 1.2 +/- 0.3 u./pmol. Subcellular fractionations of PMNs revealed the recovered LTD4-to-LTE4 converting activity, termed LTD4 dipeptidase, to be localized only in he granule fraction. There was a time- and calcium-dependent extracellular release of LTD4 dipeptidase in association with lysozyme (r = 0.97, n = 16, P less than 0.001), a constituent of both specific and azurophilic granules, in the absence of release of cytoplasmic lactate dehydrogenase (LDH) and of beta-glucuronidase from the azurophilic granule. Phorbol myristate acetate (PMA), which selectively induces secretion of specific granules, released lysozyme and the LTD4 dipeptidase in a constant dose-dependent manner from PMNs (r = 0.96, n = 8, P less than 0.001). Calcium ionophore A23187 at concentrations less than 10(-7) M stimulated the parallel secretion of LTD4 dipeptidase and lysozyme (r = 0.91, n = 9, P less than 0.005), dipeptidase and lysozyme (r = 0.91, n = 9, P less than 0.005), whereas higher concentrations resulted in secretion of beta-glucuronidase and additional lysozyme without further release of dipeptidase. Thus, human PMNs can convert LTD4 to LTE4, a less vasoactive and spasmogenic leukotriene, via the secretion of a dipeptidase associated with the specific granules.

Cells, Cultured↗
PubMed1994

Molecular cloning of sheep lung dipeptidase: a glycosyl phosphatidylinositol-anchored ectoenzyme that converts leukotriene D4 to leukotriene E4.

Sheep lung dipeptidase was released from a plasma membrane preparation by digestion with a phosphatidylinositol-specific phospholipase C. The dipeptidase was purified to homogeneity using affinity chromatography followed by high performance liquid chromatography. The NH2-terminal sequence was determined and employed to prepare a probe to clone the c-DNA of the enzyme. The primary structure of sheep lung dipeptidase, deduced from the c-DNA exhibited a high homology to kidney dipeptidases cloned from other animal species. Northern analysis detected the m-RNA of the dipeptidase in lung, kidney, and intestinal tissues of the sheep.

Amino Acid Sequence↗
PubMed1984

Identification of leukotriene D4 receptor binding sites in guinea pig lung homogenates using [3H]leukotriene D4.

We have characterized [3H]leukotriene D4 binding to guinea pig lung homogenates. Both biphasic dissociation kinetics and curvilinear Scatchard plots indicated the presence of [3H]leukotriene high and low affinity states of the binding sites. The rank order of potency for the competition study was leukotriene C4 = leukotriene D4 greater than leukotriene E4 much greater than arachidonic acid, and for their contractile effect on lung strips was leukotriene C4 = leukotriene D4 = leukotriene E4 much greater than arachidonic acid. FPL-55712 was the only other agent tested that inhibited binding. These results suggest that binding of [3H]leukotriene D4 to the homogenate is consistent with its binding to specific leukotriene D4 receptor sites.

Animals↗
PubMed1990

SK&F S-106203 inhibits leukotriene C4, leukotriene D4 and leukotriene E4 vasopressor responses in the conscious rat.

1. The purpose of these experiments was to investigate the effects of the selective peptidoleukotriene receptor antagonist, SK&F S-106203, on leukotriene C4 (LTC4), LTD4 and LTE4 vasopressor responses in the conscious, normotensive rat. SK&F S-106203 was administered as a bolus followed by a continuous infusion in order to provide information on the relationship between antagonism of leukotriene responses and steady-state plasma concentrations. 2. Infusion of SK&F S-106203 at doses of 0.2 mgkg-1 + 1 mgkg-1 h-1, 1 mgkg-1 + 3 mgkg- h-1 or 2 mgkg-1 + 10 mgkg-1 h-1 produced dose-dependent steady-state plasma drug concentrations of 1.0, 3.2 and 23.8 micrograms ml-1, respectively. Plasma SK&F S-106203 concentrations appeared to increase in a linear fashion at doses of 1 and 3 mgkg-1 h-1; at the highest dose the increment in plasma drug concentrations (i.e., 7-8 fold) was greater than the increment in dose (i.e., 3 fold), suggesting saturation of the primary clearance mechanism(s) at this dose. 3. SK&F S-106203 (2 mgkg-1 + 10 mgkg-1 h-1) had no effect on noradrenaline-, vasopressin-, isoprenaline-, or U 46619-induced responses. 4. SK&F S-106203 produced dose-dependent rightward shifts in the LTC4 and LTE4 dose-response curves. Administration of SK&F S-106203 at doses of 0.2mg kg1 + 1 mg kg1 h-, mg kg' + 3mgkg-'h-1, or 2mgkg-' + lOmgkg-1h'- produced dose-ratios of 1.0, 3.1 and 19.9, respectively, against LTC4 responses, and dose-ratios of 1.6, 3.8 and 9.1, respectively, against LTE4 responses. 5. Against LTD4 responses, SK&F S-106203 at doses of 0.2mgkg- + mgkg-1 h-, mg kg' + 3 mg kg- 1h - ', or 2 mg kg- + 10 mg kg- h- produced dose-ratios of 2.5, 2.8, and 11.4, respectively. Administration of D-penicillamine, a non-competitive LTD4 dipeptidase inhibitor, had no effect on LTD4 responses. 6. The similarity in the LTD4 dose-ratios at the two lower infusion rates, despite increases in the plasma drug concentrations, suggests the existence of pharmacologically heterogeneous LTD4 receptors. These results indicate that SK&F S-106203 is a potent, selective and apparently competitive antagonist of LTC4, LTD4 and LTE4 vascular responses in the intact rat.

Animals↗
PubMed1990

ICI 198615 is an antagonist of leukotriene C4, leukotriene D4 and leukotriene E4 vasopressor responses in the conscious rat.

The purpose of these studies was to evaluate the effects of the peptidoleukotriene (LT) receptor antagonist, ICI 198615, on the vasopressor responses produced by LTC4, LTD4 and LTE4. Conscious, normotensive rats were prepared with arterial and venous catheters for measurement of changes in arterial blood pressure and administration of drugs, respectively. Complete dose-response curves were first generated to LTC4, LTD4 and LTE4: those agents produced dose-dependent increases in arterial blood pressure, with ED20 values (i.e. dose to increase blood pressure 20 mm Hg) of 1.7 +/- 0.2, 2.1 +/- 0.2 and 19.8 +/- 3.7 nmol/kg i.v., respectively. ICI 198615 (intravenous bolus followed by a continuous infusion) produced dose-dependent, parallel shifts to the right in the LTC4 dose-response curve. At doses of 0.2 mg/kg + 1 mg/kg/h, 1 mg/kg + 3 mg/kg/h or 2 mg/kg + 10 mg/kg/h, ICI 198615 produced dose ratios of 4.5, 17.1 and 50.0, respectively. Against LTD4 responses, ICI 198615 at a dose of 0.1 mg/kg + 0.3 mg/kg/h produced a dose ratio of 3.4, whereas at doses of 0.2 mg/kg + 1 mg/kg/h, 1 mg/kg + 3 mg/kg/h or 2 mg/kg + 10 mg/kg/h ICI 198615 produced dose ratios of 16.3, 24.9 and 16.2, respectively. The difference in the dose ratios between these three groups was not statistically significant (p greater than 0.05). However, a dose of 10 mg/kg + 30 mg/kg/h produced a dose ratio of greater than 100. Against LTE4 responses, ICI 198615 at doses of 0.2 mg/kg + 1 mg/kg/h or 1 mg/kg + 3 mg/kg/h produced dose ratios of 4.1 and 11.3, respectively. The similarity in the LTD4 dose ratios despite a 3- or 10-fold increase in the dose of ICI 198615 suggests the existence of high- and low-affinity LTD4 receptor sites, whereas the responses to LTC4 and LTE4 appeared to be mediated via a single receptor population. These results indicate that ICI 198615 is a potent and competitive antagonist of LTC4, LTD4 and LTE4 vascular responses in the rat.

Animals↗
PubMed1989

Reversal of leukotriene D4- and leukotriene E4-induced airway constriction in the guinea pig.

Conscious Hartley guinea pigs were challenged with LTD4 or LTE4 aerosols. When dynamic compliance (Cdyn) decreased to 50% of its baseline value, the challenge aerosols were stopped and treatment aerosols of salbutamol, the LTD4/E4 antagonist LY171883 Na, atropine, or sodium chloride (control) were begun. After 5 min of continuous exposure to the treatment aerosol, each animal was killed and excised lung gas volume (ELGV) was measured. Salbutamol was equally effective in reversing LTD4- and LTE4-induced Cdyn changes. Aerosolized LY171883 Na was effective against both agonists, but was about threefold more potent against LTE4. In contrast, atropine was very effective in reversing LTD4-induced Cdyn changes, but produced minimal reversal when LTE4 was the challenge agent. Pulmonary gas trapping results supported these observations; ELGV values were closely correlated with 5-min Cdyn measurements for both LTD4 (r = -0.817) and LTE4 (r = -0.831). Thus, although LTD4 and LTE4 are though to act on the same or similar receptors, the pattern of pharmacologic reversal at comparable levels of airway obstruction differs for these two agonists.

Acetophenones↗
PubMed1993

Characterization of the leukotriene D4 receptor in dimethylsulphoxide-differentiated U937 cells: comparison with the leukotriene D4 receptor in human lung and guinea-pig lung.

The leukotriene D4 receptor has been fully characterized by radioligand binding in membrane preparations from dimethyl sulphoxide-differentiated U937 cells, a human monocyte leukemia cell line, and, in parallel experiments, compared with leukotriene D4 receptor found in human lung and guinea-pig lung preparations. [3H]Leukotriene D4 specific binding in differentiated U937 cell membranes is of high affinity (KD = 0.35 nM), saturable (Bmax = 287 fmol/mg protein), with differentiation resulting in a 3-5-fold increase in the number of detectable binding sites. [3H]Leukotriene D4-specific binding in differentiated U937 cell membranes displays several features of G-protein-coupled receptors, being inhibited by GTP analogues and sodium ions, but increased by divalent cations. These characteristics are shared with [3H]leukotriene D4-specific binding in human and guinea-pig lung preparations. However, differences between these leukotriene D4 receptor types were observed. [3H]Leukotriene D4 equilibrium binding to differentiated U937 cell membranes could be dissociated to non-specific binding levels by 1000-fold excess of competing ligand, whereas binding to guinea-pig lung membranes was only partially dissociated under these conditions. In addition, differences in potency were demonstrated in competition studies with leukotriene E4 and leukotriene C4, although leukotriene D4 and the leukotriene D4-receptor antagonists MK-571 and ICI 204,219 were equipotent in competing for [3H]leukotriene D4-specific binding in all three membranes preparations. In conclusion, the leukotriene D4 receptor in differentiated U937 cell membranes resembles that in human lung, validating the use of this cell line as a suitable source of receptor in the development of potent specific antagonists.

Animals↗
PubMed1987

Interaction between leukotriene D4 and adenosine or iloprost in the isolated working guinea-pig heart: prevention of the leukotriene D4 effect.

The interaction between leukotriene D4 and adenosine or the prostacyclin analogue iloprost was studied in isolated guinea-pig hearts. Adenosine (1 X 10(-6) M) or iloprost (5 X 10(-8) M) abolished or greatly attenuated the vasoconstrictive effect of leukotriene D4 over a wide dose range of leukotriene D4 (0.01-1000 ng), and myocardial ischemia as a consequence of coronary insufficiency completely disappeared. Comparison of myocardial levels of reduced pyridine nucleotide fluorescence in hearts treated with leukotriene D4 and in hearts subjected to varying degrees of high-flow hypoxia, or the calcium agonist BAY-K 8644, revealed low levels of reduced pyridine nucleotides in the leukotriene D4-treated hearts, suggesting that leukotriene D4 directly suppressed myocardial contractility. These findings were supported by full restoration of cardiac work by the receptor antagonist FPL 55712 following leukotriene D4 treatment. It is concluded that adenosine and iloprost are potent inhibitors of leukotriene D4-induced reduction in coronary flow in guinea-pig hearts, and that myocardial ischaemia and suppressed cardiac work are prevented during leukotriene D4 study in adenosine or iloprost perfused hearts. Low levels of myocardial-reduced pyridine nucleotides during leukotriene D4 treatment and restoration of cardiac work by FPL 55712 indicate that leukotriene D4 may also have a direct suppressive effect on myocardial contractility.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Effect of RG 12525, an oral leukotriene D4 antagonist, on the airway response to inhaled leukotriene D4 in subjects with mild asthma.

We have studied the effect of RG 12525, an oral leukotriene D4 (LTD4) antagonist, on LTD4-induced bronchoconstriction in eight male subjects with mild asthma (baseline FEV1 greater than 80% predicted) in a double-blind, placebo-controlled fashion. RG 12525 800 mg displaced the dose-response curve for LTD4 to the right. The mean (95% confidence intervals) difference in log PC20FEV1 following RG 12525 and placebo was 2.88 (1.61, 4.17) doubling doses of LTD4 (P less than 0.01), a 7.5 fold difference. We conclude that RG 12525 when administered orally is an effective LTD4 antagonist in subjects with mild asthma.

Administration, Oral↗
PubMed1989

Effect of the oral leukotriene D4 antagonist LY171883 on inhaled and intradermal challenge with antigen and leukotriene D4 in atopic subjects.

Sulfidopeptide leukotrienes have been suggested as potential mediators of the bronchoconstriction of asthma. The effect of the orally active leukotriene D4 (LTD4) antagonist LY171883 (LY) (400 mg) on antigen or LTD4-induced bronchoconstriction and wheal-and-flare responses was studied in atopic subjects on six occasions (three groups of 2 consecutive days). On the first 2 study days, subjects were screened for their response to inhaled LTD4 and antigen. On the second and third groups of 2 study days, subjects received LY, 400 mg, or placebo 2 hours before inhaled leukotriene LTD4 or antigen challenge. After antigen challenge, the lung function was measured for 6 hours. After the inhaled challenge, intradermal LTD4 and antigen challenges were performed. LY had no effect on baseline lung function. Geometric mean (95% confidence intervals) for the provocative dose of LTD4 causing a 40% fall in forced expiratory flow at 40% vital capacity from a forced expiratory flow maneuver was 1.8 (0.5 to 5.6) nmol after placebo and 5.6 (2.0 to 15.7) nmol after LY. This difference was not significant. The mean maximum change during the early phase of antigen-induced bronchoconstriction was reduced, being 54.7 (26.9% to 82.4%) after placebo and 35.8 (2.3% to 69.3%) after LY (p less than 0.05). There was, however, no difference in the maximum response observed during the late phase. There was also a significant reduction in the area under the curve of the early but not late-phase response to antigen. LY significantly shifted the intradermal LTD4 dose-response curve for both wheal and flare to the right (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetophenones↗
PubMed1987

SKF 104353, a high affinity antagonist for human and guinea pig lung leukotriene D4 receptor, blocked phosphatidylinositol metabolism and thromboxane synthesis induced by leukotriene D4.

SKF 104353 (2(S)-hydroxyl-3(R)-carboxyethylthio)-3-[2-(8-phenyloctyl) phenyl] propanoic acid) is a synthetic structural analog of leukotrienes D4 and E4 (LTD4, LTE4). This compound binds to guinea pig and human lung LTD4 receptors with affinities (Ki) of 5 +/- 2 and 10 +/- 3 nM, respectively. The Ki values of a reference compound, FPL 55712, were 2200 and 4500 nM, respectively, approximately 400- and 500-fold less effective than SKF 104353. LTD4- and LTE4-induced biosynthesis of thromboxane B2 has been shown to be mediated by LTD4 receptors in guinea pig lung in vitro. SKF 104353 did not induce synthesis of TxB2 in this system at concentrations of 1-20 microM. When SKF 104353 and increasing concentrations of LTD4 were incubated with guinea pig lung, the dose response curve of LTD4-induced TxB2 biosynthesis was shifted to the right with a -log[KB] = 8.4 +/- 0.2. LTD4-induced phosphatidylinositol (PI) hydrolysis in guinea pig lung has been shown to be the major signal transduction mechanism. In this system, SKF 104353 (1-20 microM) did not promote PI hydrolysis. Pretreatment of the [3H]myo-inositol-labeled guinea pig lung with SKF 104353 shifted the LTD4-induced PI hydrolysis dose response curve to the right, indicating that SKF 104353 inhibited LTD4 receptor-mediated intracellular second messenger formation. These results demonstrate that SKF 104353 is a high affinity, specific LTD4 receptor antagonist. It inhibited LTD4-induced PI hydrolysis and TxB2 biosynthesis in guinea pig lung. SKF 104353 may prove to be an important research tool for research on the activities of leukotrienes and of value therapeutically in the treatment of leukotriene-mediated diseases.

Animals↗
PubMed1988

Effect of a novel leukotriene D4 antagonist with 5-lipoxygenase and cyclooxygenase inhibitory activity, Wy-45,911, on leukotriene-D4-and antigen-induced bronchoconstriction in the guinea pig.

Wy-45,911 (4-[hydroxy-[3-(2-quinolinylmethoxy)phenyl] amino]-4-oxabutanoic acid, methyl ester) was found to inhibit competitively leukotriene D4 (LTD4)-induced contractions of the isolated guinea pig trachea but not those of leukotriene C4 (LTC4), even in the presence of a gamma-glutamyltranspeptidase inhibitor, reduced glutathione (GSH). Tracheal contractions induced by histamine or pilocarpine were also not significantly altered by Wy-45,911. The drug inhibited the tracheal contractions induced by antigen, even in the presence of GSH. This latter effect resulted from inhibition of 5-lipoxygenase (5-LO), as the synthesis of 5-LO products by rat polymorphonuclear leukocytes and by mouse macrophages was markedly reduced by Wy-45,911. The drug inhibited both LTD4-induced and antigen-induced bronchoconstriction when injected intraduodenally or intragastrically into intact guinea pigs though it was more potent against LTD4-induced bronchoconstriction. We conclude that Wy-45,911 is a novel, orally active LTD4 antagonist in the guinea pig, with some 5-LO inhibitory activity.

Animals↗
PubMed1991

Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene D4 receptor antagonists. 4. Addition of chromone moiety enhances leukotriene D4 receptor binding affinity.

The combination of the benzopyran-4-one ring, a moiety found in the prototype leukotriene antagonist, FPL 55,712, with the (2-quinolinylmethoxy)phenyl group led to a significant increase in leukotriene receptor binding affinity. This modification resulted in a 10,000-fold improvement in binding affinity compared to FPL 55,712. Compound 7 (RG 12553), with a Ki value of 0.1 nM, has higher affinity than the natural agonist LTD4 and is one of the most potent LTD4 antagonists reported. The structure-activity relationships of this series of potent leukotriene antagonists are discussed.

Animals↗