title: The pharmacology of L-670,596, a potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist.
abstract: L-670,596 ((-)6,8-difluoro-9-rho-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 x 10(-9) M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC50, 1.1 x 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), U44069 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.
authors.affiliation: Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire, Canada.
authors.forename: A W
authors.initials: AW
authors.lastname: Ford-Hutchinson
authors.forename: Y
authors.initials: Y
authors.lastname: Girard
authors.forename: A
authors.initials: A
authors.lastname: Lord
authors.forename: T R
authors.initials: TR
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Cirino
authors.forename: J F
authors.initials: JF
authors.lastname: Evans
authors.forename: J
authors.initials: J
authors.lastname: Gillard
authors.forename: P
authors.initials: P
authors.lastname: Hamel
authors.forename: C
authors.initials: C
authors.lastname: Leveillé
authors.forename: P
authors.initials: P
authors.lastname: Masson
mesh_terms: D000758:Anesthesia; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D009130:Muscle, Smooth / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D011449:Prostaglandin Endoperoxides / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects; D013552:Swine; D013931:Thromboxanes / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects
chemical_list: D002227:Carbazoles; D010975:Platelet Aggregation Inhibitors; D011449:Prostaglandin Endoperoxides; D011982:Receptors, Prostaglandin; D013931:Thromboxanes; C061299:L 670596