Novel fluorinated benzyloxyphenyl piperidine-4-carboxamides were identified as promising lead compounds with dual antithrombotic function inhibiting both FXa and platelet aggregation.
These leads merit further preclinical validation; leaves open dual antithrombotic potential in clinical thrombosis.
A series of benzyloxy anilides of nipecotic (5, 6) and isonipecotic (7, 8) acids were synthesized and assayed in vitro as inhibitors of ADP-induced platelet aggregation and the blood coagulation enzymes factor Xa (FXa) and thrombin (FIIa). An exploration of effects of the amidine group attached at the piperidine nitrogen, position and substitution (F, phenyl) of the benzyloxy group, and addition of fluorine/s on the second (distal) phenyl ring, led us to single out some promising isonipecotamide derivatives 7. Addition of meta-F and para-CF(3) on the distal phenyl ring resulted in a 6-to-18-fold enhancement of the FXa potency and in 2-to-4-fold increase of the antiplatelet potency, the last depending to a large extent upon lipophilicity. Two congeners of N-{[3-(1,1'-biphenyl-4-yl)methoxy]phenyl}piperidine-4-carboxamide (7m and 7p) proved to be potent FXa-selective inhibitors (K(i) = 130 and 57 nM, respectively) and antiplatelet agents and were identified as leads for developing new dual function antithrombotic drugs.
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Candia et al. (2009) studied this question.
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