Biarylmethoxy isonipecotanilides as potent and selective inhibitors of blood coagulation factor Xa.
New chloro-substituted biarylmethoxyphenyl piperidine-4-carboxamides were synthesized and assayed in vitro as inhibitors of the blood coagulation enzymes factor Xa (fXa) and thrombin. An investigation of effects of the amidine and isopropyl groups attached at the piperidine nitrogen and 5-(halogenoaryl)isoxazol-3-yl groups as biaryl substituents led us to identify new compounds which proved to be selective fXa inhibitors, with inhibition constants in the low nanomolar range. The most potent compound 21e, that incorporates 2-Cl-thiophen-5-yl group as the P1 motif and 1-isopropylpiperidine P4 group, inhibited fXa with K(i) value of 0.3nM and very high selectivity over thrombin and some other tested serine proteases, achieving moderate levels of anticoagulant activity in the low micromolar range, as assessed by the prothrombin time clotting assay (PT(2)=3.30μM). Based on reliable docking simulations, molecular modeling provided a rationale for interpreting structure-activity relationships. The predicted binding modes highlighted the structural requirements for addressing the subsites S1 and S4 of the fXa enzyme.
Dipartimento Farmaco-Chimico, University of Bari, Via E. Orabona 4, I-70125 Bari, Italy.
Gianfranco
G
Lopopolo
Filomena
F
Fiorella
Modesto
M
de Candia
Orazio
O
Nicolotti
Sophie
S
Martel
Pierre-Alain
PA
Carrupt
Cosimo
C
Altomare
D000813:Anilides / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D000813:Anilides; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors