“…Anagrelide ( 1 ) is a potent inhibitor of blood platelet aggregation (BPA) in platelet-rich plasma (PRP) from rats, dogs, rhesus monkeys, and humans that protects against activation induced by a broad range of physiologically relevant stimuli, including adenosine diphosphate (ADP), collagen, arachidonic acid, and thrombin, with EC 50 values of <1 μg/mL. , BL-3459 ( 2 ), the prototype 1,2,3,5-tetrahydroimidazo[2,1- b ]quinazolin-2-one, was discovered 50 years ago at Bristol Laboratories in Syracuse, New York when J. Stuart Fleming and his team conducted a phenotypic screening campaign that used ADP-induced rabbit PRP to identity effective platelet aggregation inhibitors. , Although 2 was subjected to extensive preclinical profiling, development was ultimately suspended following the observation of microcrystals of the 7-hydroxy metabolite in the livers of dogs during preclinical toxicology studies, a finding that led to the selection of 1 , where the 7-position is blocked, for clinical evaluation. , As a potent and broad-spectrum inhibitor of rabbit and human BPA in PRP, 1 was readily distinguished from the most prominent antiplatelet agents at that time, aspirin, sulfinpyrazone, and dipyridamole, each of which exhibited inhibitory activity toward a much narrower range of stimuli (Table ). Following oral dosing of 1 to rats and dogs, BPA measured ex vivo in response to collagen or ADP was inhibited with ED 50 values ranging from 0.29 to 4.86 mg/kg, with the half-lives of the biological effect amounting to 7 h in the rat and 19 h in the dog .…”