New NO-donors with antithrombotic and vasodilating activities, Part 16. 3-Amino-1,2,4-oxadiazol-5-ones as prodrugs for hydroxyguanidines.

ABSTRACT

Nineteen 4-substituted 1,2,4-oxadiazol-5-ones (6a-s) were prepared as prodrugs for lipophilic hydroxyguanidines which should be metabolized in vivo to nitric oxide. This hypothesis was tested indirectly by measuring the antithrombotic properties of these compounds 2 h after oral administration to rats (60 mg/kg). In mesenteric arterioles seven compounds moderately (> or = 10%) inhibited the formation of thrombi by a laser beam. Maximum effects were observed in 6c (4-pentyl) and 6f (4-benzyl). The lack of activity in the corresponding 2-pentyloxadiazolone 10c, where no formation of nitric oxide seems possible, indirectly suggests that the antithrombotic properties of the title compounds could be mediated by the in vivo formation of nitric oxide.