PULMONARY PHARMACOLOGY OF DT-TX-30-SE, A POTENT SELECTIVE COMBINED THROMBOXANE SYNTHETASE INHIBITOR AND RECEPTOR ANTAGONIST, IN GUINEA-PIGS

A novel chemical compound, DT-TX 30 SE onylamino)-ethyl)phenyl)-6-(3-p yridyl)-hex-5-enoic acid), was studied in various models of guinea pig pulmonary function. The compound was a potent inhibitor (ED(50) 0.019 mg/kg, i.v.) of bronchospasm induced by the thromboxane receptor agon ist U-46619, indicating thromboxane receptor antagonism. At even lower doses (ED(50) 0.0036 mg/kg, i.v.), it blocked arachidonic acid-induce d bronchospasm. Interpretation of the latter results as evidence for a dditional thromboxane synthetase inhibitory activity was supported by the inhibition of arachidonic acid- or bradykinin-induced thromboxane B-2 production in an isolated lung preparation, although prostaglandin E(2) and prostaglandin 6-oxo-F-1 alpha production measured at the sam e time were not inhibited. The potency of DT-TX 30 SE was compared wit h thromboxane receptor antagonists and synthetase inhibitors described in the literature. As a receptor antagonist, DT-TX 30 SE was signific antly more potent than BM 13505 and BM 13177 (assessed by antagonism o f U-46619-induced bronchospasm), but less potent than SQ 29548, while as a thromboxane synthetase inhibitor, it was significantly more poten t than OKY 046 and UK 37248 as assessed by antagonism of arachidonic a cid-induced bronchospasm or (OKY 046) inhibition of thromboxane produc tion in isolated lung. The compound was active by the oral route as sh own by its ability, at 10 mg/kg, p.o., to significantly reduce the imm ediate allergic response of sensitized guinea pigs to an ovalbumin aer osol.