Jpn. J. Pharmacol. 71 (2), 119-127 (1996)

Pulmonary Pharmacology of DT-TX 30 SE, a Potent Selective Combined Thromboxane Synthetase Inhibitor and Receptor Antagonist, in Guinea Pigs

Christopher J. Meade (1), Gojko Muacevic (1), Paul Ward (2) and Rainer Soyka (3)

(1) Department of Biological Research, Boehringer Ingelheim KG, D-55216 Ingelheim/Rhein, Germany (2) Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, U.K. (3) Department of Chemistry, Dr. Karl Thomae GmbH, Biberach a.d. Riss, Germany

Abstract: A novel chemical compound, DT-TX 30SE (E-6-(4-(2-(4-chlorobenzenesulphonylamino)- ethyl)phenyl)-6-(3-pyridyl)-hex-5-enoic acid), was studied in various models of guinea pig pulmonary function. The compound was a potent inhibitor (ED50 0.019 mg/kg, i.v.) of bronchospasm induced by the thromboxane receptor agonist U-46619, indicating thromboxane receptor antagonism. At even lower doses (ED50 0.0036 mg/kg, i.v.), it blocked arachidonic acid-induced bronchospasm. Interpretation of the latter results as evidence for additional thromboxane synthetase inhibitory activity was supported by the inhibition of arachidonic acid- or bradykinin-induced thromboxane B2 production in an isolated lung preparation, although prostaglandin E2 and prostaglandin 6-oxo-F1alpha production measured at the same time were not inhibited. The potency of DT-TX 30 SE was compared with thromboxane receptor antagonists and synthetase inhibitors described in the literature. As a receptor antagonist, DT-TX 30 SE was significantly more potent than BM 13505 and BM 13177 (assessed by antagonism of U-46619-induced bronchospasm), but less potent than SQ 29548, while as a thromboxane synthetase inhibitor, it was significantly more potent than OKY 046 and UK 37248 as assessed by antagonism of arachidonic acid-induced bronchospasm or (OKY 046) inhibition of thromboxane production in isolated lung. The compound was active by the oral route as shown by its ability, at 10 mg/kg, p.o., to significantly reduce the immediate allergic response of sensitized guinea pigs to an ovalbumin aerosol.

Keywords: Thromboxane, Thromboxane synthetase, Inhibitor, Thromboxane receptor antagonist, Lung

Copyright© The Japanese Pharmacological Society 1996

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