Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target

Ankrom, Wendy; Wood, Harold B.; Xu, Jiayi; Geissler, Wayne M.; Bateman, T. David; Chatterjee, Manash; Feng, Kung-I; Metzger, Joseph M.; Strapps, Walter; Tadin‐Strapps, Marija; Seiffert, Dietmar; André, Patrick

doi:10.1002/prp2.207

Cited by 16 publications

(21 citation statements)

References 23 publications

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“…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%

“…This allows for the efficient and potent antithrombotic activity of such inhibitors at very low concentrations. On the other hand, several preclinical and clinical investigations have already demonstrated a lesser risk of bleeding with the direct inhibition of FXa [22,29]. Nevertheless, the latest clinical studies have just demonstrated that Rivaroxaban and Apixaban dose interruption could produce thromboembolic events.…”

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%

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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

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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.

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Section: Theoretical Studymentioning

confidence: 74%

Section: Synthesis Of 1h-123-triazole Derivativesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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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

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“…The very high level of calculated enzyme occupancy needed for FXIIa active site inhibitors is perhaps unsurprising considering that FXIIa is the most upstream factor in the intrinsic cascade and any "leakage" with a tiny amount of FXIIa may be subsequently cascaded and amplified. One precedent of a very high level of target engagement for an active site inhibitor of a coagulation factor is apixaban, a FXa inhibitor, requiring .99% calculated enzyme occupancy to deliver clinically relevant efficacy (Ankrom et al, 2016). A third potential reason could be that thrombin-mediated activation of FXI will bypass FXII, thus requiring more complete inhibition of FXIIa and immediate shut-down of thrombin generation.…”

Section: Discussionmentioning

confidence: 99%

Factor XIIa as a Novel Target for Thrombosis: Target Engagement Requirement and Efficacy in a Rabbit Model of Microembolic Signals

Barbieri

Wang

et al. 2017

The Journal of Pharmacology and Experimental Therapeutics

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Coagulation Factor XII (FXII) plays a critical role in thrombosis. What is unclear is the level of enzyme occupancy of FXIIa that is needed for efficacy and the impact of FXIIa inhibition on cerebral embolism. A selective activated FXII (FXIIa) inhibitor, recombinant human albumin-tagged mutant Infestin-4 (rHA-Mut-inf), was generated to address these questions. rHA-Mut-inf displayed potency comparable to the original wild-type HA-Infestin-4 (human FXIIa inhibition constant = 0.07 and 0.12 nM, respectively), with markedly improved selectivity against Factor Xa (FXa) and plasmin. rHA-Mut-inf binds FXIIa, but not FXII zymogen, and competitively inhibits FXIIa protease activity. Its mode of action is hence akin to typical small-molecule inhibitors. Plasma shift and aPTT studies with rHA-Mut-inf demonstrated that calculated enzyme occupancy for FXIIa in achieving a putative aPTT doubling target in human, nonhuman primate, and rabbit is more than 99.0%. The effects of rHA-Mut-inf in carotid arterial thrombosis and microembolic signal (MES) in middle cerebral artery were assessed simultaneously in rabbits. Dose-dependent inhibition was observed for both arterial thrombosis and MES. The ED of thrombus formation was 0.17 mg/kg i.v. rHA-Mut-inf for the integrated blood flow and 0.16 mg/kg for thrombus weight; the ED for MES was 0.06 mg/kg. Ex vivo aPTT tracked with efficacy. In summary, our findings demonstrated that very high enzyme occupancy will be required for FXIIa active site inhibitors, highlighting the high potency and exquisite selectivity necessary for achieving efficacy in humans. Our MES studies suggest that targeting FXIIa may offer a promising strategy for stroke prevention associated with thromboembolic events.

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Leveraging model-informed approaches for drug discovery and development in the cardiovascular space

Dockendorf

Vargo

Gheyas

et al. 2018

J Pharmacokinet Pharmacodyn

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Cardiovascular disease remains a significant global health burden, and development of cardiovascular drugs in the current regulatory environment often demands large and expensive cardiovascular outcome trials. Thus, the use of quantitative pharmacometric approaches which can help enable early Go/No Go decision making, ensure appropriate dose selection, and increase the likelihood of successful clinical trials, have become increasingly important to help reduce the risk of failed cardiovascular outcomes studies. In addition, cardiovascular safety is an important consideration for many drug development programs, whether or not the drug is designed to treat cardiovascular disease; modeling and simulation approaches also have utility in assessing risk in this area. Herein, examples of modeling and simulation applied at various stages of drug development, spanning from the discovery stage through late-stage clinical development, for cardiovascular programs are presented. Examples of how modeling approaches have been utilized in early development programs across various therapeutic areas to help inform strategies to mitigate the risk of cardiovascular-related adverse events, such as QTc prolongation and changes in blood pressure, are also presented. These examples demonstrate how more informed drug development decisions can be enabled by modeling and simulation approaches in the cardiovascular area.

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Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target

Cited by 16 publications

References 23 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

Factor XIIa as a Novel Target for Thrombosis: Target Engagement Requirement and Efficacy in a Rabbit Model of Microembolic Signals

Leveraging model-informed approaches for drug discovery and development in the cardiovascular space

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