Antithrombotic effects of LB30870, a potent, orally active, selective and direct thrombin inhibitor, and pharmacokinetics of its prodrug

Park, Hee Dong; Lee, Sung-Hack; Kim, Tae Hoon; Lee, Sun Hwa; Cho, Kwan Hyung; Kim, Aeri

doi:10.1016/j.bmcl.2013.07.008

Cited by 10 publications

(8 citation statements)

References 32 publications

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“…In other studies already reported, FXa-, thrombin-, and plasma-induced endothelial inflammatory gene expressions were suppressed by direct oral anticoagulants such as another FXa inhibitor rivaroxaban, and of the reported genes, MCP-1 was one of those most strongly related (Ellinghaus et al, 2016; Seki et al, 2017). Therefore, besides the previous findings, our study confirmed the anti-inflammatory effect of TAK-442, and reconfirmed that endothelial MCP-1 production was induced by FXa independently of thrombin, through a comparative study using melagatran, which is a selective inhibitor for thrombin over other serine proteases (greater than 1000-fold) except for trypsin (Park et al, 2013).…”

Section: Discussionsupporting

confidence: 86%

TAK-442, a Direct Factor Xa Inhibitor, Inhibits Monocyte Chemoattractant Protein 1 Production in Endothelial Cells via Involvement of Protease-Activated Receptor 1

2018

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Oral blood coagulation inhibitors and their receptors, such as factor Xa (FXa), thrombin, and the thrombin receptor protease-activated receptor 1 (PAR1), are entered into clinical trials for acute coronary syndrome therapy; however, the results obtained so far are different for each drug. The underlying mechanisms of the results have not been fully investigated. We studied the in vitro anti-inflammatory effects of the selective FXa inhibitor TAK-442 on human endothelial cells, with comparing those of the selective thrombin inhibitor melagatran and the PAR1 antagonist vorapaxar. In human umbilical vein endothelial cells, FXa-increased production of monocyte chemoattractant protein 1 (MCP-1), a key inflammatory mediator, was inhibited by TAK-442 but not melagatran, and was also remarkably suppressed by vorapaxar. As thrombin did, FXa increased calcium mobilization in PAR1-overexpressed Chinese hamster ovary cells, which was selectively inhibited by TAK-442 and vorapaxar. We therefore confirmed the inhibitory effect of TAK-442 in endothelial MCP-1 production and the PAR1 intervention in the response. Our results suggest that TAK-442 may have anti-inflammatory potential in addition to its anti-thrombotic effects.

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Section: Discussionsupporting

confidence: 86%

TAK-442, a Direct Factor Xa Inhibitor, Inhibits Monocyte Chemoattractant Protein 1 Production in Endothelial Cells via Involvement of Protease-Activated Receptor 1

2018

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“…Higher Caco-2 cell permeability of LB30889 compared to LB30870 can be explained by the difference in the net charge and consequently logD at physiological pH. LB30889 has no net charge, whereas LB30870 has net positive charge at pH 7, which is reflected in their logD values of 1.74 and −0.088, respectively, as reported by Park et al LB30896, LB30917, and LB30928 can be classified as BCS II, whereas LB30908 and LB30924 are classified as BCS III. One should be careful when correlating BCS to dog PK as there is some evidence for generally better drug permeability in dogs than in humans .…”

Section: Discussionsupporting

confidence: 51%

“…Other experimental conditions were the same as above-described in the Effect of Food Composition on Oral Bioavailability of LB30870 in Dogs section. For each prodrug, plasma concentrations of the prodrug itself, its intermediate metabolite, and the active form, LB30870 as the final metabolite were determined by HPLC as described previously for LB30889 . Prodrug BAs were estimated from the AUC last of LB30870 only, and those of prodrug itself or intermediates were not included.…”

Section: Materials and Methodsmentioning

confidence: 99%

“…LB30870 is a new direct thrombin inhibitor with the chemical name 2-{[(1R)-2-((2S)-2{[({5-[amino(imino)methyl]-2-thienyl}methyl)amino]carbonyl}-pyrrolidinyl)-1-benzhydryl-2-oxoethyl]amino}acetic acid (Figure ). It was proposed as a potential therapeutic agent for the prevention and treatment of thrombotic diseases based on its anticoagulation activities and oral bioavailability (BA) in preclinical animal species. , The clearance (CL) of LB30870 after IV dosing was dose-independent within the dose range tested in rats and dogs . LB30870 was well tolerated in healthy men when given orally up to 240 mg .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Thrombin plays a key role in arterial thrombosis. Hirudin and argatroban, specific thrombin inhibitors, prevent reocclusion of coronary artery and reduce the formation of microthrombi and ischemic lesions [6]. Though hirudin is a highly specific and direct For reprint orders, please contact reprints@future-science.com inhibitor of thrombin, hirudin and its analogs have a strong anticoagulant effect, making them difficult to administer in the absence of appropriate antidotes.…”

Section: Antiplatelet Therapymentioning

confidence: 99%

Progress in the Research of GPIIb/IIIa Antagonists

et al. 2015

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This review covers the recent advances in the development of small RGD (Arg-Gly-Asp sequence) containing peptides and their mimetics as potential antithrombotic agents. Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists include monoclonal antibodies, RGD peptides, peptide hybrids and nonpeptide mimetics. The current trend in the development of nonpeptide mimetics is clearly directed toward orally active and safe antithrombotic drug candidates. But several nonpeptide mimetics, being evaluated for their oral activity in human clinical trials, are currently not approved for clinical use due to poor safety profile. It is expected that newer and more effective nonpeptide mimetics will be developed in the near future.

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Antithrombotic effects of LB30870, a potent, orally active, selective and direct thrombin inhibitor, and pharmacokinetics of its prodrug

Cited by 10 publications

References 32 publications

TAK-442, a Direct Factor Xa Inhibitor, Inhibits Monocyte Chemoattractant Protein 1 Production in Endothelial Cells via Involvement of Protease-Activated Receptor 1

TAK-442, a Direct Factor Xa Inhibitor, Inhibits Monocyte Chemoattractant Protein 1 Production in Endothelial Cells via Involvement of Protease-Activated Receptor 1

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

Progress in the Research of GPIIb/IIIa Antagonists

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