Abstract:
A series of chiral lactamcarboxamides of aminomethylpiperidine were synthesized and investigated for the collagen induced in vitro anti-platelet efficacy and collagen plus epinephrine induced in vivo pulmonary thromboembolism. The compound 31a (30 μM/Kg) displayed a remarkable antithrombotic efficacy (60% protection) which was sustained for more than 24 hours and points to its excellent bioavailability. The compounds 31a (IC50= 6.6µM) and 32a (IC50=37µM), as well as their racemic mixture 28i (IC50=16µM) significantly inhibited collagen-induced human platelet aggregation in vitro. Compound 34c displayed dual mechanism of action against both collagen (IC50=3.3µM) and U46619 (IC50=2.7M) induced platelet aggregation. The pharmacokinetic study of 31a indicated very faster absorption, prolonged and constant systemic exposure and thereby exhibiting better therapeutic response.
