Key result
Compound 4a, a newly synthesized pyrazolyl piperidine analog, displayed high in vitro factor Xa inhibition activity with an IC50 of 13.4 nM and good anticoagulation activity compared to Heparin.
Why the study?
Factor Xa is an important pharmaceutical target for the treatment of thrombotic disorders, motivating the design and synthesis of new anticoagulant drug candidates.
Do novel pyrazolyl piperidine analogs inhibit factor Xa and demonstrate anticoagulant activity in vitro?
Do novel pyrazolyl piperidine analogs inhibit factor Xa and demonstrate anticoagulant activity in vitro?
Effect estimate: IC50 13.4 nM
Compound 4a is a novel pyrazolyl piperidine analog that demonstrates potent in vitro factor Xa inhibition and anticoagulant activity, representing a potential new class of anticoagulant drug candidates.
May support preclinical development of 4a as FXa inhibitor; leaves open clinical translation pending in vivo validation.
Coagulation factor Xa (FXa), a serine endopeptidase is a common coagulation factor activated as a result of the initiation of both intrinsic and extrinsic blood coagulation pathways. Hence, FXa has been regarded as an important pharmaceutical target for the treatment of thrombotic disorders. In this study, we reported the design and synthesis of pyrazolyl piperidine analogs 4(a–h) as a new class of anticoagulant drug candidates. Among the synthesized analogs 4(a–h), compound 4a consisting of the 4-chlorophenyl substitution displayed the highest in vitro FXa inhibition activity with an IC50 value of 13.4 nM. The PT and aPTT assay indicated that compound 4a showed good anticoagulation activity compared to Heparin. Furthermore, docking studies suggested that the synthesized analogs displayed binding modes similar to the cocrystallized Rivaroxaban ligand. In addition, in-silico ADMET and DFT studies were carried out for all the designed compounds. Together, our study suggests that the compound (4a) displayed anti-coagulant activity through the inhibition of FXa.
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Rayani et al. (2022) studied Thrombotic disorders. Pyrazolyl piperidine analog 4a vs. Heparin was evaluated on In vitro FXa inhibition activity (IC50 13.4 nM). Compound 4a, a newly synthesized pyrazolyl piperidine analog, displayed high in vitro factor Xa inhibition activity with an IC50 of 13.4 nM and good anticoagulation activity compared to Heparin.
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