Pharmacological Characterization Of Potent, Long-Acting Thromboxane Receptor Antagonists, Sq-33,261 And Sq-33,552

SQ 33,261 {[1S-[1-alpha,2-alpha(Z),3-alpha,4-alpha]]-6-[3-[[2-[(phenylamino)carbonyl]hydrazono]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexen-oic acid} and SQ 33,552 {[1S-[1-alpha,2-alpha(Z),3-alpha,4-alpha]]-6-[3-[[[[(4-chlorophenyl)amino]carbonyl]hydrazono]methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-4-hexenoic acid} are potent thromboxane (Tx) A2 receptor antagonists. They inhibited platelet aggregation in platelet-rich plasma induced by the TxA2 mimetic, U-46,619 (10-mu-M), with IC50 values of 200 and 70 nM, respectively. Neither compound inhibited ADP (20-mu-M)-induced platelet aggregation (IC50 > 1000-mu-M). SQ 33,261 and SQ 33,552 competitively antagonized U-46,619-induced contraction of rat aortic strips with respective pA2 values of 9.0 and 10.1 and K(B) values of 1.2 and 0.1 nM. They also competitively antagonized U-46,619-induced contraction of guinea pig tracheal strips with pA2 values of 8.9 and 9.9 and K(B) values of 1.9 and 0.4 nM, respectively. SQ 33,261 and SQ 33,552 (p.o.) were potent inhibitors of U-46,619 (2 mg/kg i.v.)-induced death in mice with ID50 values of 8 and 1-mu-g/kg, respectively. SQ 33,261 and SQ 33,552 (0.2 mg/kg p.o.), also had long duration of action in this assay with 50% survival times of 7 and 15 hr, respectively. SQ 33,261 at 0.01 and 1.0 mg/kg i.v., inhibited arachidonic acid-induced bronchoconstriction and reversed arachidonic acid-induced hypertension to a hypotensive response. SQ 33,552 inhibited TxA2 synthase at high concentrations (IC50 = 307-mu-M), whereas SQ 33,261 was inactive. Neither compound inhibited cyclooxygenase or caused an elevation of platelet cyclic AMP levels. These data indicate that SQ 33,261 and SQ 33,552 are potent, long-acting TxA2 receptor antagonists that may be useful for the investigation and treatment of diseases involving TxA2 receptor activation.