1402905-81-0Relevant articles and documents
β-D-Glucosyl Conjugates of Highly Potent Inhibitors of Blood Coagulation Factor Xa Bearing 2-Chorothiophene as a P1 Motif
Lopopolo, Gianfranco,deCandia, Modesto,Campagna, Francesco,Altomare, Cosimo,Panza, Luigi,Romano, Maria Rosaria,Lograno, Marcello Diego
, p. 1669 - 1677,9 (2020/08/31)
We synthesized a novel O-glucoside of the recently reported potent factor Xa (fXa) inhibitor 1, which bears a 5-chlorothien-2-yl moiety and 1-isopropylpiperidine as fragments that bind the S1 and S4 enzyme pockets, respectively. A β-D-glucosyl unit was conjugated through an ether-linked C3-alkyl spacer to the central phenyl ring of 1. The synthesized β-D-glucose-based compound 16 achieved picomolar inhibitory potency against human fXa (Ki=60pM) and high selectivity over thrombin and other serine proteases. In addition to the chlorothienyl S1 binder, a large gain in ΔG resulted from the addition of protonated 1-isopropylpiperidine (ΔΔG=29.7-30.5kJmol-1), which should bind to the aromatic S4 pocket through efficient cation-π and CH{dot operator}{dot operator}{dot operator}π interactions. Instead, the C3-alkyl-linked glucose fragment, which is likely directed toward the solvent outside the enzyme binding site, improves ΔG by an average of 2.9-3.8kJmol-1. Compound 16 showed sub-micromolar invitro anticoagulant activity, as assessed by prothrombin time (PT) and activated thromboplastin time (aPTT) clotting assays in pooled human plasma (PT2 and aPTT2 equal to 0.135 and 0.389μM, respectively). Although compound 16 was 1.4-fold less active than parent compound 1 in the exvivo anticoagulant assay in mice, it showed a significant (1.6-fold) prolongation of PT relative to controls (P-1).
