Introducing suitable modifications into the structure of lipophilic nipecotic acid anilides, previously identified as in vitro inhibitors of blood platelet aggregation, we succeeded in the purpose of empowering these molecules with anticoagulant activity, achieved by the selective inhibition of factor Xa of the blood coagulation cascade..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. The combination of Fxa inhibition and platelet antiaggregatory activities into one molecule, which per se should be advantageous (as for pharmacokinetics, drug interactions and toxicity, less demanding clinical studies, etc.), can enhance its potential as antithrombotic agent in patients with prosthetic heart valves and atrial fibrillation.

Fluorinated Benzyloxyphenyl Piperidine-4-carboxamides with Dual Function against Thrombosis: Inhibitors of Factor Xa and Platelet Aggregation

CAROTTI, Andrea;
2009

Abstract

Introducing suitable modifications into the structure of lipophilic nipecotic acid anilides, previously identified as in vitro inhibitors of blood platelet aggregation, we succeeded in the purpose of empowering these molecules with anticoagulant activity, achieved by the selective inhibition of factor Xa of the blood coagulation cascade..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. The combination of Fxa inhibition and platelet antiaggregatory activities into one molecule, which per se should be advantageous (as for pharmacokinetics, drug interactions and toxicity, less demanding clinical studies, etc.), can enhance its potential as antithrombotic agent in patients with prosthetic heart valves and atrial fibrillation.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11391/42861
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