The pharmacology of L-670,596, a potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist

Abstract

L-670,596 ((−)6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid) has been shown to be a potent receptor antagonist as evidenced by the inhibition of the binding of ¹²⁵I-labeled PTA-OH to human platelets (IC₅₀, 5.5 × 10⁻⁹ M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC₅₀, 1.1 × 10⁻⁷ M), and competitive inhibition of contractions of the guinea pig tracheal chain induced by U-44069 (pA₂,9.0). The compound was also active in vivo as shown by inhibition of arachidonic acid and U-44069 induced bronchoconstriction in the guinea pig (ED₅₀ values, 0.04 and 0.03 mg/kg i.v., respectively), U-44069 induced renal vasoconstriction in the pig (ED₅₀, 0.02 mg/kg i.v.), and inhibition of ex vivo aggregation of rhesus monkey platelets to U-44069 (active 1–5 mg/kg p.o.). The selectivity of the compound was indicated by the failure to inhibit, first, ADP-induced human or primate platelet aggregation and, second, bronchoconstriction in the guinea pig in vivo and contraction of the guinea pig tracheal chain in vitro to a variety of agonists. It is concluded that L-670,596 is a potent, selective, orally active thromboxane A₂/prostaglandin endoperoxide receptor antagonist.Key words: thromboxane A₂, thromboxane antagonist, prostaglandin endoperoxides, platelet aggregation.