ORALLY-ACTIVE FIBRINOGEN RECEPTOR ANTAGONISTS .2. AMIDOXIMES AS PRODRUGS OF AMIDINES

The potent and selective GP IIb-IIIa antagonist lamifiban (1, Ro 44-98 83) is currently in clinical development as an injectable antithrombot ic agent for treating and preventing acute coronary syndromes. However , for secondary prevention of thrombotic occlusions, orally active inh ibitors are needed. By means of a prodrug strategy, the modest oral ab sorption of 1 in mice was improved by a factor of 9. In addition, thes e studies demonstrated that an amidoxime group can serve as a prodrug functionality for an amidino group. Application of this principle to t he structurally related amidino carboxylate 13 led to the amidoxime es ter 18 which was absorbed approximately 20 times better, after oral ad ministration to mice, than 13. Due to the modification of the amidino group as well as of the carboxylate group, 18 completely lost its abil ity to interact with purified platelet GP IIb-IIIa. After oral adminis tration of 18 to rats, dogs, and rhesus monkeys, the bioavailability o f the active derivative 13 was 26 +/- 5, 25 +/- 6, and 33 +/- 6%, resp ectively, and the elimination half-life was 4.1 +/- 1.7, 11.4 +/- 1.1, and 5.1 +/- 1.4 h, respectively. On the basis of these properties, th e orally active 18 (Ro 48-3657), a double prodrug of the potent and se lective non-peptide GP IIb-IIIa antagonist 13 (Ro 44-3888), was select ed as clinical candidate for evaluation as a prophylactic agent in pat ients at high risk for arterial thrombosis.