Clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban, an oral direct factor Xa inhibitor, in healthy Caucasian and Japanese subjects

Kadokura, Takeshi; Kashiwa, Makoto; Groenendaal, Dorien; Heeringa, Marten; Mol, Roelof; Verheggen, Frank; García-Hernández, Alberto; Onkels, Hartmut

doi:10.1002/bdd.1858

Cited by 12 publications

(5 citation statements)

References 20 publications

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“…Because the 1,2-phenylenediamine framework has many advantages such as less chirality, high affinity for FXa (Franciskovich et al, 2005;Koshio et al, 2005), and ease to get, meanwhile, FXa inhibitors with this structure also possess predictable pharmacokinetics (Kadokura et al, 2013a), small interactions with food (Kadokura et al, 2013b) and no inter drug interactions (Kadokura et al, 2014). Yang et al (2015b) reported on the structural characteristics of Darexaban (Iwatsuki et al, 2011) with its glucuronic acid conjugate YM-222714 (Ishihara et al, 2014), Designed a series of FXa inhibitors with 3,4-diaminobenzidine backbone.…”

Section: Diaminobenzamides Derivativesmentioning

confidence: 99%

Discovery and development of Factor Xa inhibitors (2015–2022)

Zheng

Dai

et al. 2023

Front. Pharmacol.

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As a pathological coagulation process, thrombus can lead to many serious diseases, including ischemic stroke, acute myocardial infarction (AMI), acute coronary syndrome (ACS), and deep venous thrombosis (DVT). And anticoagulant drugs are one of the most effective ways to prevent and treat these diseases. Although macromolecular anticoagulant drugs such as low molecular weight heparins (LMWHs) are widely used in the clinic, their characteristics of requiring injectable use hinder their further promotion in the clinic, and the disadvantages of oral anticoagulant drugs, such as warfarin and dabigatran etexilate, which can easily cause bleeding adverse effects, are also not addressed. Factor Xa (FXa) has gained attention because it lies at the intersection of the coagulation cascade pathways, whereas subsequently introduced Factor Xa inhibitors such as rivaroxaban and apixaban, among others, have gained market popularity because of their high potency for anticoagulation and high specificity for Factor Xa when administered orally. But some of the drawbacks that these Factor Xa inhibitors have simultaneously such as fewer indications and the lack of an effective reversal drug when bleeding occurs are urgently addressed. The development of new Factor Xa inhibitors therefore becomes one means of addressing these questions. This article summarizes the small molecule Factor Xainhibitors developed from 2015 to 2022, classifies them according to their scaffolds, focuses on the analysis of their structure-activity relationships, and provides a brief assessment of them.

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Section: Diaminobenzamides Derivativesmentioning

confidence: 99%

Discovery and development of Factor Xa inhibitors (2015–2022)

Zheng

Dai

et al. 2023

Front. Pharmacol.

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“…Food effect is a major drawback of LB30870 as a potential oral anticoagulant. A predictable dose–response relationship is one of the important requirements for new generation oral anticoagulants, which offer physicians and patients a number of alternative therapeutic agents, unlike warfarin, with no need for laboratory monitoring. , Food effect or food–drug interaction generally means BA change of a drug caused by food intake and can unintentionally reduce or increase the drug exposure, thereby resulting in therapeutic failure or increased toxicity. This may adversely affect patient care and contribute to morbidity and longer treatment time or hospitalization .…”

Section: Introductionmentioning

confidence: 99%

A Food Effect Study of an Oral Thrombin Inhibitor and Prodrug Approach To Mitigate It

Lee

Kim²,

Kim³

et al. 2016

Mol. Pharmaceutics

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LB30870, a new direct thrombin inhibitor, showed 80% reduction in oral bioavailability in fed state. The present study aims to propose trypsin binding as a mechanism for such negative food effect and demonstrate a prodrug approach to mitigate food effect. Effect of food composition on fed state oral bioavailability of LB30870 was studied in dogs. Various prodrugs were synthesized, and their solubility, permeability, and trypsin binding affinity were measured. LB30870 and prodrugs were subject to cocrystallization with trypsin, and the X-ray structures of cocrystals were determined. Food effect was studied in dogs for selected prodrugs. Protein or lipid meal appeared to affect oral bioavailability of LB30870 in dogs more than carbohydrate meal. Blocking both carboxyl and amidine groups of LB30870 resulted in trypsin Ki values orders of magnitude higher than that of LB30870. Prodrugs belonged to either Biopharmaceutical Classification System I, II, or III. X-ray crystallography revealed that prodrugs did not bind to trypsin, but instead their hydrolysis product at the amidine blocking group formed cocrystal with trypsin. A prodrug with significantly less food effect than LB30870 was identified. Binding of prodrugs to food components such as dietary fiber appeared to counteract the positive effect brought with the prodrug approach. Further formulation research is warranted to enhance the oral bioavailability of prodrugs. In conclusion, this study is the first to demonstrate that the negative food effect of LB30870 can be attributed to trypsin binding. Trypsin binding study is proposed as a screening tool during lead optimization to minimize food effect.

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“…[5] As alternatives to VKAs, direct thrombin inhibitors (DTI) and direct factor Xa inhibitors ware proved to be effective at reducing arterial and venous thrombosis in patients with cardiovascular disease because it has become evident that inhibition of factor IIa (FIIa, or thrombin) and factor Xa (FXa) is expected to reduce or prevent clotting. [6] Thrombin is a serine protease, which converts fibrinogen to fibrin and activates factor V, factor VIII and factor IX. [7] FXa belongs to a family of trypsin-like serine proteases, and plays a central role in the production of thrombin and the activation cascade of the blood coagulation system, linking the extrinsic and intrinsic activation pathways.…”

Section: Introductionmentioning

confidence: 99%

AutoGPA-Based 3D-QSAR Modeling and Molecular Docking Study on Factor Xa Inhibitors as Anticoagulant Agents

Guo

Yan

Lin

et al. 2016

MATEC Web of Conferences

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Abstract. The three-dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on a series of direct factor Xa (FXa) inhibitors using AutoGPA-based modeling method in this paper. A training set of 38 molecules and a test set containing 10 molecules were used to build the 3D-QSAR model and validate the derived model, respectively. The developed model with correlation coefficients (r 2 ) of 0.8564 and cross-validated correlation coefficients (q 2 ) of 0.6721 were validated by an external test set of 10 molecules with predicted correlation coefficient (r pred 2 ) of 0.6077. Docking study of FXa inhibitors and FXa active site was performed to check the induced pharmacophore query and comparative molecular field analysis (CoMFA) contour maps using MOE2012.10. It was proved to be coincidence with the interaction information between ligand and FXa active site and was rendered to provide a useful tool to improve FXa inhibitors.

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Clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban, an oral direct factor Xa inhibitor, in healthy Caucasian and Japanese subjects

Abstract: It is concluded that single and multiple doses of darexaban are safe and well tolerated up to 240 mg with predictable PK and PD profiles in both Caucasians and Japanese, and that ethnicity does not affect its PK, PD or tolerability.

Cited by 12 publications

References 20 publications

Discovery and development of Factor Xa inhibitors (2015–2022)

Discovery and development of Factor Xa inhibitors (2015–2022)

A Food Effect Study of an Oral Thrombin Inhibitor and Prodrug Approach To Mitigate It

AutoGPA-Based 3D-QSAR Modeling and Molecular Docking Study on Factor Xa Inhibitors as Anticoagulant Agents

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