Current status of oral anticoagulant reversal strategies: a review

Rawal, Aranyak; Ardeshna, Devarshi; Minhas, Sheharyar; Cave, Brandon; Ibeguogu, Uzoma; Khouzam, Rami N.

doi:10.21037/atm.2019.07.101

Cited by 27 publications

(21 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In order to understand the relationship between the structure and the energetic behavior of all the series, including a thermochemical analysis associated to the yield of the reactions, an optimization and reactivity indexes calculation of electronic chemical potential (μ), chemical hardness (η), and electrophilicity (ω) was performed. (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) were obtained in good to excellent yield (73-93%) using a lower loading of catalyst and in shorter reaction time (15 min) than previously reported by assisted microwave methodologies.…”

Section: Theoretical Studymentioning

confidence: 74%

“…The synthesis of novel triazoles were prepared by the 1,3-dipolar cycloaddition between the N-propargyl amines (11)(12)(13)(14) and the organic azide (24-26) catalyzed by copper nanoparticles supported on ZnO in tetrahydrofuran as solvent, triethylamine as base at 160 °C under microwave irradiation (Scheme 7) [93]. (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) were obtained in good to excellent yield (73-93%) using a lower loading of catalyst and in shorter reaction time (15 min) than previously reported by assisted microwave methodologies.…”

Section: Synthesis Of 1h-123-triazole Derivativesmentioning

confidence: 99%

“…Although these new oral anticoagulants are more efficacious than warfarin for the prevention of strokes and systemic embolism in patients with atrial fibrillation, the reversal agent Andexanet alfa has only recently been approved [35,36]. The development of antidotes for oral direct FXa inhibitors are still in the pipeline, but their expected approval for therapeutic purposes will be further beneficial to anticoagulation therapy [37,38]. Novel FXa inhibitors under development are mainly structural bioisosteres of existing drugs ( Figure 3).…”

Section: Introductionmentioning

confidence: 99%

“…Synthesis of 1H-1,2,3-triazole derivatives(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38).Compounds 27-29 (X = CH 2 ; R = H, Cl, F, respectively); 30-32 (X = N-Boc; R = H, Cl, F, respectively); 33-35 (X = S; R = H, Cl, F, respectively); 36-38 (X = O; R = H, Cl, F, respectively). Novel 1H-1,2,3-triazole derivatives…”

mentioning

confidence: 99%

See 3 more Smart Citations

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

et al. 2020

View full text Add to dashboard Cite

The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73–93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (µ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29–31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.

show abstract

Section: Theoretical Studymentioning

confidence: 74%

Section: Synthesis Of 1h-123-triazole Derivativesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Pathophysiological mechanisms of AF are associated with electrical and structural remodeling, including atrial dilatation, cellular hypertrophy, dedifferentiation, fibrosis, cell death and inflammation [1][2][3]. AF is associated with increased risk of stroke [4], and direct oral anticoagulants (DOAC) has been preferentially used over warfarin to prevent stroke [5].…”

Section: Introductionmentioning

confidence: 99%

Exploratory Analysis of Circulating miRNA Signatures in Atrial Fibrillation Patients Determining Potential Biomarkers to Support Decision-Making in Anticoagulation and Catheter Ablation

Kiyosawa

Watanabe

Morishima

et al. 2020

IJMS

View full text Add to dashboard Cite

Novel biomarkers are desired to improve risk management for patients with atrial fibrillation (AF). We measured 179 plasma miRNAs in 83 AF patients using multiplex qRT-PCR. Plasma levels of eight (i.e., hsa-miR-22-3p, hsa-miR-128-3p, hsa-miR-130a-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-148b-3p, hsa-miR-497-5p, hsa-miR-652-3p) and three (i.e., hsa-miR-144-5p, hsa-miR-192-5p, hsa-miR-194-5p) miRNAs showed positive and negative correlations with CHA2DS2-VASc scores, respectively, which also showed negative and positive correlations with catheter ablation (CA) procedure, respectively, within the follow-up observation period up to 6-month after enrollment. These 11 miRNAs were functionally associated with TGF-β signaling and androgen signaling based on pathway enrichment analysis. Seven of possible target genes of these miRNAs, namely TGFBR1, PDGFRA, ZEB1, IGFR1, BCL2, MAPK1 and DICER1 were found to be modulated by more than four miRNAs of the eleven. Of them, TGFBR1, PDGFRA, ZEB1 and BCL2 are reported to exert pro-fibrotic functions, suggesting that dysregulations of these eleven miRNAs may reflect pro-fibrotic condition in the high-risk patients. Although highly speculative, these miRNAs may potentially serve as potential biomarkers, providing mechanistic and quantitative information for pathophysiology in daily clinical practice with AF such as possible pro-fibrotic state in left atrium, which would enhance the risk of stroke and reduce the preference for performing CA.

show abstract

Quantification of direct‐acting oral anticoagulants: Application of a clinically validated liquid chromatography‐tandem mass spectrometry method to forensic cases

Wiesen

Fietz

Jübner

et al. 2020

Drug Testing and Analysis

View full text Add to dashboard Cite

In certain forensic cases, a quantification of direct‐acting oral anticoagulants (DOACs) can be necessary. We evaluate the applicability of a previously described liquid chromatography–tandem mass spectrometry (LC‐MS/MS) methodology for the determination of DOACs in plasma to postmortem specimen. Postmortem internal quality control (PIQC) samples were prepared in pooled blank postmortem heart blood, femoral blood, cerebrospinal fluid (CSF), and urine as well in plasma. To examine the application of the clinical method to forensic cases, the main validation parameters were reinvestigated using PIQC samples. Postmortem samples of 12 forensic cases with evidence of previous rivaroxaban intake and unknown bleeding disorders were analyzed. Interday variability remained within the acceptance criterion of ±15%. Matrix effects were comparable in blank plasma and postmortem matrix extracts. After 4 weeks of storage in the refrigerator, no relevant decrease of DOACs was evident. After 96 h of storage at room temperature, a slight decrease in edoxaban concentration was observed in CSF and urine, while plasma edoxaban decreased by about 50%. Median (range) rivaroxaban concentrations determined in specimen of forensic cases were as follows: heart blood (n = 6), 17.2 ng/ml (

show abstract

Current status of oral anticoagulant reversal strategies: a review

Cited by 27 publications

References 49 publications

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

Exploratory Analysis of Circulating miRNA Signatures in Atrial Fibrillation Patients Determining Potential Biomarkers to Support Decision-Making in Anticoagulation and Catheter Ablation

Quantification of direct‐acting oral anticoagulants: Application of a clinically validated liquid chromatography‐tandem mass spectrometry method to forensic cases

Contact Info

Product

Resources

About