15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and seratrodast

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Oral; Adolescent; Adult; Benzoquinones; Body Weight; Double-Blind Method; Heptanoic Acids; Humans; Leukotriene B4; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Quinones; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2

KP-496 is a novel dual antagonist for cysteinyl leukotriene receptor 1 (CysLT(1)) and thromboxane A(2) (TXA(2)) receptor (TP). The aim of this study was to evaluate the pharmacological profile of inhaled KP-496 and its effects on airway obstruction.. Antagonist activities of inhaled KP-496 were investigated using bronchoconstriction induced in guinea pigs by LTD(4) or U46619, a stable TXA(2) mimetic. Guinea pigs sensitized with injections of ovalbumin were used to assess the effects of inhaled KP-496 on bronchoconstriction induced by antigen (i.v.). Another set of guinea pigs were sensitized and challenged with ovalbumin by inhalation and the effects of inhaled KP-496 on immediate and late airway responses and airway hyperresponsiveness were investigated.. KP-496 significantly inhibited LTD(4)- and U46619-induced bronchoconstriction in a dose-dependent manner. The inhibitory effects of KP-496 (1%) were comparable to those of montelukast (a CysLT(1) antagonist, p.o., 0.3 mg kg(-1)) or seratrodast (a TP antagonist, p.o., 3 mg kg(-1)). KP-496 (1%) and oral co-administration of montelukast (10 mg kg(-1)) and seratrodast (20 mg kg(-1)) significantly inhibited antigen-induced bronchoconstriction, whereas administration of montelukast or seratrodast separately did not inhibit antigen-induced bronchoconstriction. KP-496 exhibited dose-dependent and significant inhibitory effects on the immediate and late airway responses and airway hyperresponsiveness following antigen challenge.. KP-496 exerts effects in guinea pigs which could be beneficial in asthma. These effects of KP-496 were greater than those of a CysLT(1) antagonist or a TP antagonist, in preventing antigen-induced airway obstruction.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetates; Administration, Inhalation; Administration, Oral; Airway Obstruction; Animals; Anti-Asthmatic Agents; Benzoates; Benzoquinones; Bronchoconstriction; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guinea Pigs; Heptanoic Acids; Leukotriene Antagonists; Leukotriene D4; Lung; Male; Membrane Proteins; Ovalbumin; Prostaglandin Antagonists; Quinolines; Receptors, Leukotriene; Receptors, Thromboxane A2, Prostaglandin H2; Respiratory Hypersensitivity; Sulfides; Thiazoles; Time Factors

A dry powder inhaler of KP-496 is currently in clinical development in Japan as an anti-asthmatic agent. The aim of this study was to evaluate the in vitro pharmacological profile of KP-496.. The antagonistic activities of KP-496 for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors were examined using the LTD(4)- and U46619-induced contractions of the isolated guinea pig trachea. The selectivity of KP-496 was examined using various agonist-induced contractions in the isolated guinea pig trachea.. KP-496 produced parallel rightward shifts of the LTD(4) and U46619 concentration-response curves in a concentration-dependent manner. Schild plot analyses of the antagonistic activities of KP-496 demonstrated that it is a competitive antagonist for LTD(4) and TXA(2) receptors with pA(2) values of 8.64 and 8.23, respectively. The LTD(4) antagonistic activity of KP-496 was comparable to that of pranlukast and zafirlukast but was more potent than that of montelukast. The TXA(2) antagonistic activity of KP-496 was comparable to that of seratrodast. KP-496 and seratrodast also inhibited the prostaglandin (PG) D(2)- and PGF(2alpha)-induced contractions of the isolated guinea pig trachea. KP-496 had no effect on the histamine-, acetylcholine-, serotonin- and substance P-induced contractions of the isolated guinea pig trachea.. These results indicate that KP-496 is a selective dual antagonist for LTD(4) and TXA(2) receptors. LTD(4) and TXA(2) play important roles in asthma, and antagonists for these mediators are being used for the treatment of asthma. Thus, KP-496 is expected to become a novel potent therapeutic agent for asthma.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetates; Acetylcholine; Albuterol; Animals; Atropine; Benzoquinones; Carbachol; Chromones; Cyclopropanes; Dinoprost; Drug Evaluation, Preclinical; Guinea Pigs; Heptanoic Acids; Histamine; In Vitro Techniques; Indoles; Indomethacin; Ketanserin; Ketotifen; Leukotriene Antagonists; Leukotriene D4; Male; Muscle Contraction; Muscle, Smooth; Phenylcarbamates; Powders; Procaterol; Prostaglandin Antagonists; Prostaglandin D2; Quinolines; Receptors, Thromboxane A2, Prostaglandin H2; Serotonin; Substance P; Sulfides; Sulfonamides; Tosyl Compounds; Trachea; Tryptophan

We examined whether cysteinyl leukotrienes (CysLTs) and thromboxane (TX) A2 are synergistically involved in a cedar pollen-induced allergic late phase nasal blockage in guinea pigs. Sensitized animals were repeatedly challenged by pollen inhalation once every week. Combined treatment with pranlukast (a CysLT antagonist) and seratrodast (a TXA2 antagonist) inhibited late phase nasal blockage, but the magnitude of inhibition (approximately 50%) was equal to those of the respective single treatments, suggesting that CysLTs produced late after challenge induces TXA2 production in the nasal tissue, as in the case of the lung of this species. However, pranlukast did not affect TXB2 increase in the nasal tissue. In contrast, combined intranasal instillation of LTD4 and U-46619 (a TXA2 mimetic) produced much greater nasal blockage than single administration of each agonist in sensitized animals. Therefore, allergic late phase nasal blockage should be induced by synergistic activity of CysLTs and TXA2 at the effector organ.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzoquinones; Chromones; Guinea Pigs; Heptanoic Acids; Hypersensitivity; Leukotriene D4; Leukotrienes; Male; Nasal Cavity; Thromboxane A2

Cytokines from inflammatory cells do not produce nitric oxide, but stimulate the production of nitric oxide in vascular smooth muscle cells (VSMC). Thromboxane A2 (TXA2) has been believed to have a key role in atherosclerogenesis and post-angioplasty restenosis.. To determine whether cytokine-induced nitric oxide production is regulated by the TXA2/prostaglandin H2 (PGH2) receptor.. We studied the interleukin-1beta (IL-1beta)-induced production of nitric oxide in rat VSMCs using the TXA2/PGH2 receptor antagonists, seratrodast and Bay-u3405, and an agonist, U-46619. Nitrite formation was measured colorimetrically. IL-1beta increased nitrite formation in a time-dependent manner. The nitrite concentration was 1.7 times greater in the presence of seratrodast than that without it. Nitrite accumulation was increased by Bay-u3405, but was decreased in the presence of U-46619, to 44% of that in its absence. Western and Northern blotting showed that seratrodast increased the levels of expression of inducible nitric oxide synthase (iNOS) protein and mRNA in a dose-dependent manner, whereas U-46619 decreased them. We speculated that VSMCs produced TXA2, thereby decreasing nitric oxide production; therefore we measured the accumulation of TXB2 using an enzyme immunoassay. Untreated VSMCs produced about 20 pg/mg protein of TXB2. This was increased by the addition of IL-1beta, to 152.1 +/- 43.0 pg/mg protein after a 24 h incubation; the expression of cyclooxygenase-2 (COX-2) protein was also increased, but there was no effect on the expression of COX-1 and TXA2 synthase. U-63557A, a TXA2 synthase inhibitor, increased the accumulation of nitrite to 1.3-fold that in its absence.. These data suggest that the expression of iNOS and the production of nitric oxide are regulated by the TXA2/PGH2 receptor in IL-1beta-stimulated VSMCs. The endogenous production of TXA2 by the induction of COX-2 from IL-1beta-stimulated VSMCs probably downregulated the production of nitric oxide in VSMCs. TXA2/PGH2 receptor inhibitors may contribute to the reduction in formation of atherosclerosis in lesions with vascular injury by enhancing the production of nitric oxide by VSMCs.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Benzoquinones; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Down-Regulation; Enzyme Induction; Heptanoic Acids; Interleukin-1; Isoenzymes; Male; Membrane Proteins; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; RNA, Messenger; Thromboxane A2

To identify the chemical mediators involved in the pathogenesis of allergic rhinitis, we studied the effects of the thromboxane (TX) A2 receptor antagonist seratrodast, the peptide leukotriene receptor antagonist pranlukast and the antihistamine azelastine using a guinea pig model of allergic rhinitis. In guinea pigs actively sensitized by aerosol inhalation of antigen, antigen challenge into the nasal cavity increased both the nasal vascular permeability and the intranasal pressure; it also induced swelling of the nasal mucosa, which was evaluated by magnetic resonance imaging. Both seratrodast and azelastine significantly inhibited these antigen-induced responses when the drugs were administered p.o. 1 hr before antigen challenge. Also, the TX synthetase inhibitor ozagrel reduced the antigen-induced increase in nasal vascular permeability. On the other hand, pranlukast had little effect on the antigen-induced increases in nasal vascular permeability and intranasal pressure. Perfusions and inhalations of U-46619, a stable TXA2 mimetic, or of histamine into the nasal cavity caused concentration-dependent increases in nasal vascular permeability and intranasal pressure in normal guinea pigs. Leukotriene C4 also induced these responses, but the maximal responses to leukotriene C4 were less than the maximal responses to U-46619 or histamine. On the other hand, these responses were not induced by prostaglandin D2 or prostaglandin F2alpha. Moreover, the U-46619- and histamine-induced increases in vascular permeability and intranasal pressure were significantly inhibited by seratrodast and azelastine, respectively. In addition, levels of TXB2, a stable breakdown product of TXA2, and histamine in nasal lavage fluid increased after antigen challenge in actively sensitized guinea pigs. These results suggest that TXA2 and histamine play important roles in the pathogenesis of experimental allergic rhinitis in guinea pigs.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antigens; Benzoquinones; Capillary Permeability; Guinea Pigs; Heptanoic Acids; Histamine; Histamine H1 Antagonists; Male; Nasal Mucosa; Phthalazines; Prostaglandin Antagonists; Prostaglandin Endoperoxides, Synthetic; Rhinitis, Allergic, Seasonal; Thromboxane A2

The human thromboxane A2 receptor (TXA2-R)-coding gene was introduced into Chinese hamster ovary cells and a cell line (TCHO-25) stably expressing TXA2-R, at a level of 3 x 10(5)/cell, was obtained. An anti-asthmatic agent AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7- phenylheptanoic acid] competitively inhibited the specific binding of a TXA2 mimic ([3H]U-46619) to the TCHO-25 cells, with an IC50 of 6.0 x 10(-8) M, indicating that the drug is an antagonist of human TXA2-R. The TCHO-25 cells offer a tool for the screening and characterization of human TXA2-R antagonists.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Asthma; Benzoquinones; Binding, Competitive; CHO Cells; Cloning, Molecular; Cricetinae; Guinea Pigs; Heptanoic Acids; Humans; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Plasmids; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Thromboxane A2; Trachea

The effects of a novel TXA2 receptor antagonist, AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinone-2-yl)-7-phenyl-heptanoic acid], on U-46619-, PGD2- and 9 alpha, 11 beta-PGF2 alpha-induced contractions of isolated guinea pig tracheas and human bronchi were investigated. AA-2414 competitively inhibited the contractile responses of both human and guinea pig preparations induced by U-46619 with similar pA2 values (7.7 and 7.6, respectively). In addition, the compound also inhibited the contractions of both preparations caused by PGD2 and 9 alpha, 11 beta-PGF2 alpha, the IC50 values of which were 1.2 x 10(-7) and 1.8 x 10(-7) M in guinea pig tracheas and 2.8 x 10(-8) and 8.5 x 10(-8) M in human bronchi. These results suggest that AA-2414 may be a therapeutically useful drug for bronchial asthma.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzoquinones; Bronchi; Dinoprost; Guinea Pigs; Heptanoic Acids; Humans; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; Quinones; Receptors, Thromboxane; Thromboxane A2; Trachea

Consideration of possible structural similarities between thromboxane A2 and the hydroquinone form of (R)-(+)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7- phenylheptanoic acid (R-(+)-AA-2414) led to the development of a new series of thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonists, namely 7-(4-fluorophenyl)-7-(2-hydroxyphenyl)heptanoic acids (I). These compounds were found to be potent TXA2/PGH2 receptor antagonists. Compounds having either a carbonyl or a hydroxymethyl group at the para-position of the phenolic hydroxy group exhibited most potent activities in this series. Compounds 14, 15, 18, and 26 inhibited the specific binding of [3H]U-46619 to guinea pig platelet membranes (IC50 = 4.4, 80, 32, and 13 nM, respectively), and also inhibited U-46619-induced human platelet aggregation (IC50 = 310, 69, 79, and 78 nM, respectively). Comparison of the UV spectra of the compounds with a carbonyl group at the para-position of phenolic hydroxy group revealed that the activity tended to increase in accordance with a decrease in the torsional angle between the carbonyl group and the phenol ring. These results suggested that the spacial location of the carbonyl and hydroxymethyl oxygen are important for significant increase in activity and that the carbonyl and hydroxymethyl oxygen at the para-position of the phenolic hydroxy group might interact with one of the TXA2/PGH2 receptor sites.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Benzoquinones; Blood Platelets; Bronchoconstriction; Cell Membrane; Fluorobenzenes; Guinea Pigs; Heptanoic Acids; Humans; Hydroquinones; Male; Molecular Structure; Muscle Contraction; Phenols; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Quinones; Rabbits; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Spectrophotometry, Ultraviolet; Structure-Activity Relationship

AA-2414, (+/-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoi c acid, inhibited the aggregation of guinea pig platelets induced by a prostaglandin endoperoxide (PGH2) analogue, U-44069 and the specific binding of another analogue, [3H]U-46619 to washed guinea pig platelets with IC50 values of 3.1 x 10(-7) and 8.2 x 10(-9) M, respectively. AA-2414 competitively inhibited the contraction of rabbit aorta and pig coronary arteries induced by U-44069 with pA2 values of 8.3 and 9.0, respectively. AA-2414 also inhibited the contraction of rabbit aorta induced by PGF2 alpha (pA2: 7.8) and the contraction of pig coronary arteries induced by PGF2 alpha, PGD2 and 9 alpha,11 beta-PGF2 with pA2 values of 7.8, 8.6 and 7.8, respectively. But, AA-2414 had no effect on the antiaggregatory effect of PGD2 on the aggregation of guinea pig platelets. In experiments with guinea pigs ex vivo, AA-2414 (0.1-1 mg/kg, p.o.) dose-dependently inhibited the platelet aggregation induced by U-44069; the inhibition at a dose of 1 mg/kg was 100% at 1 hr and was 89% even at 24 hr after the administration. The thromboxane (TX) A2/PGH2 receptor antagonistic action of AA-2414 was stereospecific. These results show that AA-2414 is a potent, orally active and long acting TXA2/PGH2 receptor antagonist. In addition, AA-2414 has PGF2 alpha, PGD2 and 9 alpha,11 beta-PGF2 antagonistic effects.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzoquinones; Blood Platelets; Dinoprost; Eicosanoids; Epoprostenol; Guinea Pigs; Heptanoic Acids; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; Quinones; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Stereoisomerism; Swine

The anti-asthmatic activity of AA-2414 [(+/-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano ic acid] has been studied in vivo and in vitro. Experimental allergic asthma was inhibited by orally administered AA-2414 in a dose-dependent manner. AA-2414, 0.08-1.25 mg/kg (p.o.), inhibited the bronchconstriction in guinea pigs induced by a prostaglandin endoperoxide analogue (U-46619), leukotriene D4 (LTD4), and platelet activating factor (PAF) with a long duration of action. The compound did not inhibit histamine-induced bronchoconstriction. AA-2414 reduced the induction of pulmonary inflation caused by LTD4 aerosol inhalation. AA-2414 competitively inhibited the contractile response to U-46619 in guinea pig tracheal and parenchymal strips and dog saphenous vein strips with pA2 values of 7.69, 8.29 and 6.79, respectively. Furthermore, the contractile responses of guinea pig tracheal strip to PGD2, 9 alpha, 11 beta-PGF2 and PGF2 alpha were inhibited with pA2 values of 7.20, 7.79 and 5.71, respectively. These results suggest that AA-2414, a quinone derivative, is a novel, potent and orally active antagonist of a variety of spasmogenic prostanoids.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Administration, Oral; Animals; Asthma; Benzoquinones; Dogs; Dose-Response Relationship, Drug; Guinea Pigs; Heptanoic Acids; Histamine Antagonists; Male; Platelet Activating Factor; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; Quinones; Rabbits; Rats; Rats, Inbred Strains; SRS-A; Trachea