Randall Mj

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

Abstract 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 TxB2 production, IC50 = 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 (PGI2) synthesis by pig aortic microsomes. Evidence for a re-direction of arachidonate (AA) metabolism from Tx-synthesis towards PGI2 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 PGI2 and other PGs. In anaesthetised rabbits, fifteen minutes after injection of 0.3mg/kg i.v. UK-37,248, TxB2 production was 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 = 4.8×10−6M). UK-37,248, 2mg/kg p.o. prevented AA-induced mortality in rabbits and reduced the associated thrombosis, vasospasm and elevation of plasma TxB2.

Piroxicam, a structurally novel anti-inflammatory compound. Mode of prostaglandin synthesis inhibition

Piroxicam is a potent inhibitor of prostaglandin biosynthesis. Experiments utilizing cell culture and microsomes derived from various sources have demonstrated that piroxicam is a selective inhibitor of the cyclooxygenase step of arachidonic acid metabolism. Little blocking activity is observed at the phospholipase, thromboxane or prostacyclin synthetase, and arachidonic acid lipoxygenase steps.

Selective inhibition of thromboxane synthesis with dazoxiben in animals and man

z include stimulation of PGI2 synthesis (perhaps leading to a rise in CAMP levels), preservation of PC1 or selective inhibition of thromboxane synthe ~s~:ockWaedehaofeT~~~s~~~~~~of~; fourth approach. We anticipated that a selective inhibitor of thromboxane synthetase would not only inhibit production of TxA but also would preserve or even enhance production of prostacyclin un ike 5.. the non-steroidal anti-inflammatory agents that inhibit both platelet and vascular cycle-oxygenase. The possibility of such an inhibition increasng PG12 synthesis was based upon the observations that blood vessel segments use platelet-derived prostaglandin (PG) endoperoxides to synthesize PGI when thromboxane production is inhibited (2). Therefore, a number of s udies z