L-641,953 (R-8-fluoro-dibenzo[b, f]thiepin-3-carboxylic acid-5-oxide): a novel thromboxane–prostaglandin endoperoxide antagonist

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Abstract
The effects of L-641,953 (R-8-fluoro-dibenzo[b,f]thiepin-3-carboxylic acid-5-oxide) have been studied on pulmonary and other smooth muscle preparations in vitro and in vivo. When studied in vitro on guinea-pig tracheal chains. L-641,933 produced significant shifts in the dose-response curves to the prostaglandin endoperoxide analogues. U-44069 (pA2 7.06) and U-46619 (pA2 7.14), and prostaglandin (PG) F2.alpha. (pA2 6.33) had minimal activity against contractions induced by histamine (pA2 4.38), 5-hydroxytryptamine (pA2 4.63), and acetylcholine (pA2 4.56) and slightly enhanced relaxation induced by PGE2. When tested on the guinea-pig gall bladder strip in vitro, L-641,953 antagonized contractions induced by U-44069 (pA2 7.03) but was less active against those induced by PGF2.alpha. (pA2 6.03), PGE1 (pA2 5.62), and histamine (pA2 4.84). When tested in vitro on the guinea-pig pulmonary artery, L-651-953 significantly antagonized contractions induced by U-44069 (pA2 7.04), U-46619 (pA2 7.14), and PGF2.alpha. (pA2 7.16) but was less effective against contractions induced by histamine (pA2 4.19). Schild analysis indicated that L-641,953 was fully competitive against contractions of either the guinea-pig tracheal chain induced by U-46619 or the guinea-pig pulmonary artery induced by U-44069 and U-46619. When tested on human platelets in vitro L-641,953 inhibited aggregation induced by U-44069 (ED50 0.026 mg/kg) but not histamine in the guinea pig and U-44069 (ED50 0.15 mg/kg) but not histamine or PGF2.alpha. in the dog. When L-641,953 was administered by the intraduodenal route to dogs (3 mg/kg) significant inhibition of bronchoconstriction induced by U-44069 or arachidonic acid was observed with a duration of action .gtorsim. 3 h. It is concluded that L-641,953 is a novel, relatively selective, and orally active antagonist of the thromboxane-prostaglandin endoperoxide receptor.