UK-37,248, A novel, selective thromboxane synthetase inhibitor with platelet anti-aggregatory and anti-thrombotic activity

UK-37,248, 4-[-2-(1H-imidazol-1-yl)ethoxy] benzoic acid hydrochloride, in a human platelet microsomal preparation of thromboxane (Tx) synthetase, potently inhibited TxB 2 production, IC 50 = 3×10 −9M. In contrast, prostaglandin (PG) endoperoxide synthesis from ram seminal vesicle microsomes was unaffected by concentrations of UK-37,248 up to 1×10 −4M. Similarly UK-37,248 had minimal effects upon prostacyclin (PGI 2) synthesis by pig aortic microsomes. Evidence for a re-direction of arachidonate (AA) metabolism from Tx-synthesis towards PGI 2 synthesis was obtained using a rabbit isolated perfused lung preparation. Concentrations of UK-37,248 from 10 −7 − 10 −6M infused into the pulmonary artery selectively reduced TxA2 production from AA but increased the release of PGI 2 and other PGs. In anaesthetised rabbits, fifteen minutes after injection of 0.3mg/kg i.v. UK-37,248, TxB 2 production was reduced by 75%. In dogs the compound was similarly effective, lmg/kg p.o. inhibiting TxB 2 production by 79% two hours after dosing. Aggregation of human platelet-rich plasma in vitro , initiated by threshold collagen, was inhibited by UK-37,248 (IC 50 = 4.8×10 −6M). UK-37,248, 2mg/kg p.o. prevented AA-induced mortality in rabbits and reduced the associated thrombosis, vasospasm and elevation of plasma TxB 2.