Design, Synthesis, and Biological Activity of Potent and Selective Inhibitors of Blood Coagulation Factor Xa

Abstract

Factor Xa (FXa) has materialized as a key enzyme for the intervention of the blood coagulation cascade and for the development of new antithrombotic agents. FXa is the lone enzyme responsible for the production of thrombin and therefore is an attractive target for the control of thrombus formation. We have designed and synthesized a unique series of quinoxalinone FXa inhibitors. This series resulted in 3-[4-[5-((2S,6R)-2,6-dimethylpiperidin-1-yl)pentyl]-3-oxo-3,4-dihydroquinoxolin-2-yl]benzamidine (35) with 0.83 nM activity against FXa and excellent selectivity over similar serine proteases. An X-ray crystal structure of compound 35 bound to trypsin along with molecular modeling has led to a predicted binding conformation of compound 35 in FXa. Compound 35 has also been proven to be efficacious in vivo in both the rabbit veno-venous shunt and dog electrolytic injury models. In addition, it was shown that compound 35 did not significantly increase bleeding times in a rabbit model except at the highest doses and plasma concentrations were elevated in a dose dependent manner following a bolus dose and continuous intravenous infusion.

Radiation-induced reduction of quinoxalin-2-one derivatives in aqueous solutions

“…Quinoxaline-2-one derivatives are particularly interesting since some of them showed a variety of pharmacological properties, such as antimicrobial (Ajani et al, 2010;El-Sabbagh et al, 2009;Sanna et al, 1998;Sanna et al, 1999), antiviral (Xu et al, 2009), antifungal (Carta et al, 2002;Ingale et al, 2007;Sanna et al, 1999), anxiolytic (Ulrich et al, 1998), analgesic (Ingale et al, 2007), antiinflammatory (El-Sabbagh et al, 2009), antithrombotic (Ries et al, 2003;Willardsen et al, 2004), and antitumor (Hirai et al, 2011;Koth et al, 2007;Lawrence et al, 2001;Meyer et al, 2006) activities. Based on the computer modeling and "in vitro" studies, quinoxalin-2-ones have been proposed as potential drugs in treatments of various diseases (Carta et al, 2006).…”

Efficient syntheses of isotopically labeled PD0198961, a novel synthetic coagulation factor Xa inhibitor

“…3 The step (5-6) for installing the aryl nitrile functionality was considered to introduce the 14 C radiolabel. However, the sequence of the original synthesis was not suitable to prepare radioactive labeled compounds.…”

Cinnamylindoline Derivatives: Synthesis and Factor Xa (FXa) Inhibitory Activities

“…We speculate that the hydroxyl group at the 2-position of the benzene ring makes a hydrogen bond with Ser 195, whereas it makes a water-mediated hydrogen bond, a relatively indirect interaction, with Ser 195 in the S1 pocket of trypsin. [16][17][18][19] It seems that this difference leads to both potent FXa inhibitory activity and the enzyme selectivity. On the other hand, the methoxy group of 22b makes it difficult to interact with the S1 pocket of both FXa and trypsin, so this caused a significant decline of inhibitory activity.…”