Nonpeptide Factor Xa Inhibitors: DPC423, a Highly Potent and Orally Bioavailable Pyrazole Antithrombotic Agent

Abstract

DPC423, 1‐[3‐(aminomethyl)phenyl]‐N‐[3‐fluoro‐2′‐(methylsulfonyl)[1,1′‐biphenyl]‐4‐yl]‐3‐(trifluoromethyl)‐1H‐pyrazole‐5‐carboxamide, is a synthetic, orally bioavailable, competitive, and selective inhibitor of human coagulation factor Xa (Ki [nM]: factor Xa, 0.15; trypsin, 60; thrombin, 6000; plasma kallikrein, 61; activated protein C, 1800; factor IXa, 2200; factor VIIa, >15,000; chymotrypsin, >17,000; urokinase, >19,000; plasmin, >35,000; tissue plasminogen activator, >45,000; complement factor I, 44,000 [IC50]). In vitro, DPC423 produced anticoagulant effects in human plasma in which it doubled prothrombin time, activated partial thromboplastin time, and Heptest clotting time at 3.1 ± 0.4, 3.1 ± 0.4, and 1.1 ± 0.5 μM, respectively. In dogs, DPC423 had a good pharmacokinetic profile with an oral bioavailability of 57%, a plasma clearance of 0.24 L/kg/h, and a plasma half‐life of 7.5 h. In rabbit and rat models of arteriovenous shunt thrombosis, DPC423 was an effective antithrombotic agent with an IC50 of 150 and 470 nM, respectively. The antithrombotic effect of DPC423 is likely to be related to the inhibition of factor Xa but not to the inhibition of thrombin or due to direct inhibition of platelet aggregation. Therefore, based on potency, selectivity, efficacy, and oral bioavailability, DPC423 was selected for clinical development as an oral anticoagulant for the potential treatment of thrombotic disorders. Preliminary human data suggest that DPC423 is orally bioavailable in humans and has a long plasma half‐life.

Correlation of Coagulation Markers and 4F-PCC-Mediated Reversal of Rivaroxaban in a Rabbit Model of Acute Bleeding

“…Furthermore, rabbit models have been found to be suitable models for assessment of FXa inhibitors. This is because they are comparable to humans in terms of in vitro anticoagulation effect of FXa inhibitors [43], and are more sensitive to small molecule FXa inhibitors than mice, rats or dogs [44,45]. In addition, the use of a randomised design and of both placebo and negative control groups allowed for a rigorous evaluation of rivaroxaban reversal with 4F-PCC.…”

Metabolism, pharmacokinetics and pharmacodynamics of the factor Xa inhibitor apixaban in rabbits

“…In general, rabbits are a more sensitive model to small molecule FXa inhibitors than mice, rats or dogs [8,28,29] and have therefore been widely used as thrombosis disease models (i.e., arteriovenous-shunt thrombosis, venous thrombosis and electrolytic-injured carotid arterial thrombosis) in studies looking at the antithrombotic efficacy of FXa inhibitors [8,28]. Furthermore, our study has also demonstrated that the rabbit model is comparable to humans in terms of in vitro anticoagulation effect of FXa inhibitors.…”

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

“…As a result, compound 65 was selected for clinical development. 141,142 In effort to further optimize the selectivity, various substitutions on P1 were explored based on 65. The search led to 66 (DPC 602; fXa K i 5 0.91 nM, fIIa K i 5 3,600 nM, trypsin K i 5 3,500 nM), which has an ortho-substituted methylamine instead of the meta-substitution found in 65.…”