Inhibition of prostaglandin biosynthesis by SQ 28,852, A 7-oxabicyclo-[2.2.1]heptane analog

Abstract

7-Oxabicyclo[2.2.1]heptane analogs of prostaglandin (PG) H 2 can act as thromboxane (Tx) A 2 receptor antagonists or agonists, PGI 2 and/rr PGD 2 receptor agonists, or exhibit a mixture of the above activities. SQ 28,852, a new analog with a hexyloxymethyl omega side chain, is a potent inhibitor of PG synthesis. SQ 28,852 inhibited collagen and arachidonic acid (AA)-induced platelet aggregation and TxB 2 and PGE 2 formation, but did not block platelet aggregation induced by ADP or the TxA 2 mimics, 9,11-azoPGH 2, SQ 26,655, and U-46,619. It also blocked conversion of AA to TxB 2, PGE 2, and 6-ketoPGF 1α by microsomal preparations of human platelets, bovine seminal vesicles, and bovine aortas, respectively, but did not inhibit the conversion of PGH 2 to TxA 2 by the platelet microsomal preparation. SQ 28,852 (p.o.) protected mice against the lethal effects of AA (75 mg/kg, i.v.). The I 50 values for SQ 28,852, indomethacin and aspirin were 0.025, 0.05 and 15 mg/kg, respectively. Neither SQ 28.852 nor indomethacin protected mice from death caused by 9,11-azoPGH 2. SQ 28,852 (0.01 to 1 mg/kg, i.v.) inhibited AA-induced bronchoconstriction in anesthetized guinea pigs for at least 60 min. As an inhibitor of AA-induced bronchoconstriction, SQ 28,852 was 16- and 45-times more potent than indomethacin at 3 and 60 min after i.v. administration, respectively. SQ 28,852 did not inhibit brochoconstriction induced by histamine or 9.11-azoPGH 2, indicating its specificity of action in vivo . SQ 28,852 is the first example of a new class of cyclooxygenase inhibitors whose structure is similar to that of the naturally occurring endoperoxide, PGH 2.