benzofurans and ozagrel

Synthesis and pharmacological evaluation of novel indazole derivatives are described. These compounds were found to exhibit both thromboxane A2 (TXA2) synthetase-inhibitory and bronchodilatory activities. This observation supports the idea that the partial structure of the 3-pyridyl and phenyl groups with a methylene insertion is an important component for well-balanced activities.

Topics: Administration, Oral; Aminophylline; Animals; Benzofurans; Bronchodilator Agents; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine Antagonists; In Vitro Techniques; Indazoles; Male; Methacrylates; Pentanoic Acids; Pyridines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thromboxane-A Synthase; Trachea

Platelet-activating factor (PAF) has recently been described as a mediator of inflammatory processes. In this study, we quantitated the dose-response effects of topically applied PAF on microvascular permselectivity and investigated the biochemical pathways of this compound. Permselectivity alterations were assessed by measuring the clearance of macromolecules with fluorescein isothiocyanate dextran 150 (FITC-dx 150) as a tracer. The microvascular bed of the hamster cheek pouch served as a model. PAF was found to induce leakage of macromolecules from postcapillary venules. Control FITC-dx 150 plasma clearance (+/- SEM) was 72 +/- 10 nl/90 min. Clearances of 61 +/- 10 474 +/- 145, 622 +/- 57, 301 +/- 86, and 142 +/- 3 nl/90 min were obtained at PAF concentrations of 10(-9), 10(-8), 10(-7), 10(-6), and 10(-5) M, respectively. A one-way analysis of variance showed that the population means were not equal. Multiple comparison by the Student-Newman-Keuls test demonstrated that the clearances obtained with 10(-8), 10(-7), and 10(-6) M were significantly greater than controls. Significant differences existed between 10(-7) M PAF and 10(-9), 10(-6), and 10(-5) M PAF. In an effort to elucidate the biochemical pathways of PAF activity, several inhibitors of the arachidonic acid cascade and receptor blockers were used. Dexamethasone and kadsurenone attenuated the clearance response to PAF in a statistically significant manner, while indomethacin, OKY-046, and chlorpheniramine were without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzofurans; Blood Pressure; Capillary Permeability; Cheek; Cricetinae; Dexamethasone; Dextrans; Dose-Response Relationship, Drug; Fluorescein-5-isothiocyanate; Fluoresceins; Hematocrit; Indomethacin; Lignans; Macromolecular Substances; Male; Mesocricetus; Methacrylates; Microcirculation; Platelet Activating Factor

Pretreatment with the thromboxane synthase inhibitor OKY-046 but not the cyclo-oxygenase inhibitor ibuprofen protects against ischemia-induced acute tubular necrosis. However, ibuprofen together with the vasodilating agent prostaglandin E1 is protective. This suggests that a high prostaglandin to thromboxane ratio is the major factor operative in preventing tubular necrosis, the subject of this study. Rats that had unilateral nephrectomy (n = 60) with the exception of rats that had sham operations (n = 8) underwent 45 minutes of left renal pedicle clamping. Thirty minutes before the operation, the rats received either a saline solution or a thromboxane synthase inhibitor that was given intravenously. The inhibitors OKY-046 (2 milligrams per kilogram, n = 10), UK38485 (1 milligram per kilogram, n = 9) and U63357A (10 milligrams per kilogram, n = 10) were given as a single bolus while the inhibitor CGS13080 (0.1 milligram per kilogram, n = 9, and 1.0 milligram per kilogram, n = 7) was given by constant infusion and continued for 60 minutes after reperfusion. With saline solution therapy, five minutes after reperfusion, thromboxane B2 increased from 154 to 2,537 picograms per milliliter (p less than 0.00001) and 6-keto-prostaglandin F1 alpha increased from 51 to 266 picograms per milliliter (p less than 0.004). At 24 hours, the creatinine level increased from 0.5 to 2.8 milligrams per deciliter (p less than 0.00001). Only OKY-046 yielded a creatinine level at 24 hours of 1.2 milligrams per deciliter, a value lower than that for those in the saline solution control group (p less than 0.002). Furthermore, OKY-046 led to the highest prostaglandin to thromboxane ratio (p less than 0.035). The five other ratios which occurred after drug therapy were inversely related to the decrease in the creatinine value (r = -0.93, p less than 0.02). Histologically, OKY-046 was the only thromboxane synthase inhibitor to prevent acute tubular necrosis (p less than 0.05). Results show that a high prostaglandin to thromboxane ratio protects against acute tubular necrosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Benzofurans; Creatinine; Evaluation Studies as Topic; Ibuprofen; Imidazoles; Ischemia; Kidney; Kidney Tubular Necrosis, Acute; Male; Methacrylates; Pyridines; Rats; Thromboxane B2; Thromboxane-A Synthase

The myotropic activities of PAF-acether, leukotriene B4, leukotriene D4 and histamine were compared on superfused guinea-pig lung parenchymal strip and were shown to have the following order of potency: PAF-acether greater than LTD4 greater than LTB4 greater than histamine. The contractile response of the lung parenchyma to PAF-acether was inhibited by aspirin, imidazole and OKY-046, which suggested that thromboxane A2 might play a mediator role in PAF-induced contractions. Neither an antagonist of leukotriene D4, FPL-55712, nor an antihistamine, mepyramine, had any effect on PAF contractions. The activity of a novel antagonist of PAF-acether, BN 52021, was also studied on superfused lung parenchyma contracted by histamine, leukotriene B4, leukotriene D4 and PAF-acether. This compound was without effect on the histamine response but it slightly reduced the contractions elicited by leukotriene D4 and potentiated those by leukotriene B4. BN 52021 (7.1 X 10(-6) M) inhibited by 63% the contraction induced by 5.7 X 10(-13) M PAF-acether and by 52% that induced by 5.7 X 10(-10) M PAF-acether and kadsurenone (8.4 X 10(-6) M), another PAF-acether antagonist, inhibited the same PAF-induced contractions by 75% and 20% respectively.

Topics: Animals; Aspirin; Benzofurans; Chromones; Diterpenes; Ginkgolides; Guinea Pigs; Histamine; Imidazoles; Lactones; Leukotriene B4; Lignans; Lung; Male; Methacrylates; Muscle Contraction; Muscle, Smooth; Plant Extracts; Platelet Activating Factor; Prostaglandin Antagonists; Pyrilamine; SRS-A