UK-37,248, A Novel, Selective Thromboxane Synthetase Inhibitor With Anti-Aggregatory And Anti-Thrombotic Activity

UK-37,248, 4-(2-(lH-imidazol-l-yl)ethoxy)benzoic acid hydrochloride, potently inhibited human blood platelet microsomal thronfooxane (Tx) synthetase, IC₅₀=3xl0^-9M. TxB₂ was quantitated by a specific radioimmunoassay (RIA). In contrast (PG) endoperoxide synthesis by ram seminal vesicle microsomes and prostacylclin (PGI₂) synthesis by pig aortic microsomes/were minimally affected by concentrations of UK-37,248 up to 1x10^-4M. In the rabbit isolated perfused lung arachidonic acid (AA) metabolites were quantitated by differential bioassay. Concentrations of UK-37,248 from 10^-7-10^-6M selectively reduced TxA₂ production from AA but increased the release of PGI₂ and other PGs.

The effect of UK-37,248 in the whole animal was studied by estimating TxB₂ levels in blood samples removed before and after dosing. The samples were allowed to clot and the serum TxB₂ levels were assessed by RIA. In anaesthetised rabbits, 15 minutes after injection of 0.3mg/kg i.v. UK-37,248, serum TxB₂ levels were reduced by 75%. In dogs the compound was similarly effective, lmg/kg p.o. inhibiting TxB₂ 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 (IC₅₀=4.8x10^-6M). In rabbits, UK-37,248 at 2mg/kg i.v. prevented the mortality due to pulmonary embolism and reduced the associated thrombocytopenia and elevation of plasma TxB₂ caused by i.v. AA. In conclusion, UK-37,248 is a selective inhibitor of platelet Tx-synthetase with antiaggregatory and anti-thrombotic activity.