Nonpeptide Factor Xa Inhibitors III: Effects of DPC423, an Orally-Active Pyrazole Antithrombotic Agent, on Arterial Thrombosis in Rabbits

SummaryWe examined the antithrombotic activity of a novel synthetic inhibitor of factor Xa, YM-60828, in an electrically-induced carotid artery thrombosis model in rats. In the first experiment, the antithrombotic activity of YM-60828 after i.v. infusion was compared with those of heparin, darteparin and argatroban. Test drug was administered by i.v. infusion from 30 min before electrical stimulation to the end of the experiment. YM-60828 at 1 mg/kg/h significantly improved patency status, prolonged the time to occlusive thrombus formation and duration of patency. Heparin at 300 U/kg/h also improved these parameters, but were accompanied by a marked increase in systemic coagulation time. In the second experiment, the antithrombotic activity of YM-60828 after oral administration was compared with those of ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate and warfarin. Test drug was orally administered to fasted rats 60 min before electrical stimulation. YM-60828 at 30 mg/kg p.o., but not ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate or warfarin, significantly reduced the incidence of occlusion and improved carotid arterial patency. These results suggest that YM-60828 may be a promising antithrombotic agent for the treatment and prevention of arterial thrombosis which can be given by oral as well as intravenous administration.

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Discovery of sulfonylalkylamides: A new class of orally active factor Xa inhibitors

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2007.11.073 ◽

2008 ◽

Vol 16 (5) ◽

pp. 2243-2260 ◽

Cited By ~ 9

Author(s):

Yasuhiro Imaeda ◽

Toshio Miyawaki ◽

Hiroki Sakamoto ◽

Fumio Itoh ◽

Noriko Konishi ◽

...

Keyword(s):

Factor Xa ◽

Factor Xa Inhibitors ◽

Active Factor ◽

New Class ◽

Orally Active

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Discovery of piperazinylimidazo[1,2-a]pyridines as novel S4 binding elements for orally active Factor Xa inhibitors

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2007.12.024 ◽

2008 ◽

Vol 16 (6) ◽

pp. 3125-3140 ◽

Cited By ~ 15

Author(s):

Yasuhiro Imaeda ◽

Tetsuji Kawamoto ◽

Mamoru Tobisu ◽

Noriko Konishi ◽

Katsuhiko Hiroe ◽

...

Keyword(s):

Factor Xa ◽

Factor Xa Inhibitors ◽

Active Factor ◽

Orally Active

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Prothrombin Complex Concentrate Reverses the Anticoagulant Effect of Rivaroxaban In Healthy Volunteers.

Blood ◽

10.1182/blood.v116.21.1094.1094 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1094-1094 ◽

Cited By ~ 3

Author(s):

Elise S Eerenberg ◽

Meertien K Sijpkens ◽

Pieter W Kamphuisen ◽

Joost CM Meijers ◽

Marcel Levi

Keyword(s):

Research Funding ◽

Prothrombin Complex Concentrate ◽

Controlled Trial ◽

Factor Xa ◽

Anticoagulant Effect ◽

Factor Xa Inhibitors ◽

Specific Factor ◽

Antithrombotic Agent ◽

Double Blind ◽

Pharmacodynamic Profile

Abstract Abstract 1094 Background: Rivaroxaban is a novel oral antithrombotic agent in the class of specific factor Xa inhibitors, and is licensed in Europe and Canada for the prevention of venous thromboembolism after elective orthopedic surgery. Despite its stable pharmacokinetic and pharmacodynamic profile, immediate reversal may be required in case of a major bleeding or emergency surgery. No specific antidote is currently available, although Prothrombin Complex Concentrate (PCC) seems effective in animal studies. This study is the first to investigate the ability of PCC to reverse the antithrombotic effect of Rivaroxaban in humans. Methods: In a randomized, double-blind, placebo-controlled trial, twelve healthy male subjects received Rivaroxaban 20mg twice daily for two and a half days. One group (n=6) was then randomized to receive a single bolus of 50 IU/kg PCC (Co-fact®, Sanquin, the Netherlands) while the other group (n=6) was given a similar volume of saline. Results: The prothrombin time (PT) was significantly prolonged by Rivaroxaban (15.8 sec ± 1.3 versus 12.3 ± 0.7 at baseline; p< 0.001). Immediately after the infusion of PCC, the PT normalised almost completely (12.8 ± 1.0; p< 0.001), which was sustained for 24 hours. Saline did not reverse the PT prolongation (16.2 ± 0.8; p= 0.4). Furthermore, Rivaroxaban inhibited the endogenous thrombin potential (ETP) (51% ± 22, baseline 92 ± 22; p= 0.002), with normalisation after administration of PCC (114 ± 26; p< 0.001), but not after saline (41 ± 6; p= 0.2). Conclusions: This study provides the first data that Prothrombin Complex Concentrate reverses the anticoagulant effect of Rivaroxaban in humans and may serve as an antidote for the new oral factor Xa inhibitors. Disclosures: Eerenberg: Sanquin Netherlands: Research Funding, make available of Prothrombin Complex Concentrate for this study. Kamphuisen:Sanquin Netherlands: Research Funding, make available of Prothrombin Complex Concentrate for this study. Levi:Sanquin Netherlands: Research Funding, make available of Prothrombin Complex Concentrate for this study.

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Orally active zwitterionic factor Xa inhibitors with long duration of action

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2011.10.021 ◽

2011 ◽

Vol 21 (24) ◽

pp. 7337-7343 ◽

Cited By ~ 2

Author(s):

Akiyoshi Mochizuki ◽

Tsutomu Nagata ◽

Hideyuki Kanno ◽

Daisuke Takano ◽

Masamichi Kishida ◽

...

Keyword(s):

Factor Xa ◽

Factor Xa Inhibitors ◽

Duration Of Action ◽

Long Duration ◽

Orally Active

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Orally active factor Xa inhibitors: 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine derivatives

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2004.03.036 ◽

2004 ◽

Vol 14 (11) ◽

pp. 2935-2939 ◽

Cited By ~ 16

Author(s):

Noriyasu Haginoya ◽

Syozo Kobayashi ◽

Satoshi Komoriya ◽

Yumiko Hirokawa ◽

Taketoshi Furugori ◽

...

Keyword(s):

Factor Xa ◽

Factor Xa Inhibitors ◽

Pyridine Derivatives ◽

Active Factor ◽

Orally Active

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Synthesis and structure–activity relationship of potent, selective and orally active anthranilamide-based factor Xa inhibitors: Application of weakly basic sulfoximine group as novel S4 binding element

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2012.10.005 ◽

2012 ◽

Vol 58 ◽

pp. 136-152 ◽

Cited By ~ 25

Author(s):

Vrajesh Pandya ◽

Mukul Jain ◽

Ganes Chakrabarti ◽

Hitesh Soni ◽

Bhavesh Parmar ◽

...

Keyword(s):

Factor Xa ◽

Structure Activity Relationship ◽

Factor Xa Inhibitors ◽

Activity Relationship ◽

Structure Activity ◽

Relationship Of ◽

Orally Active

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Reversing targeted oral anticoagulants

Hematology ◽

10.1182/asheducation-2014.1.518 ◽

2014 ◽

Vol 2014 (1) ◽

pp. 518-523 ◽

Cited By ~ 4

Author(s):

Maureane Hoffman ◽

Dougald M. Monroe

Keyword(s):

Factor Viia ◽

Oral Anticoagulants ◽

Factor Xa ◽

Novel Oral Anticoagulants ◽

Factor Xa Inhibitors ◽

Invasive Procedures ◽

Prothrombin Complex Concentrates ◽

Reversal Agents ◽

Life Threatening ◽

Orally Active

Abstract Dabigatran, rivaroxaban, and apixaban are orally active anticoagulants that are approved in many countries. Dabigatran inhibits thrombin, whereas rivaroxaban and apixaban are factor Xa inhibitors. In clinical trials, these novel oral anticoagulants were at least as effective as warfarin for preventing stroke in patients with atrial fibrillation, but with a lower rate of serious bleeding. However, the lack of true antidotes for these agents has caused concern when patients suffer life-threatening bleeding or trauma or require emergent invasive procedures. True antidotes are under development for all of these agents. In the meantime, activated and nonactivated prothrombin complex concentrates have been used as reversal agents. Factor VIIa may also be effective for reversal of the factor Xa inhibitors. Reversal of novel oral anticoagulants by these hemostatic agents has not been studied in bleeding human patients, so their true efficacy and appropriate dosing are not known.

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