Application of a compound in the preparation of drugs for treating arrhythmias

Abstract

This invention belongs to the field of biomedical technology, specifically relating to the application of a compound in the preparation of drugs for treating arrhythmias. In vivo animal experiments have demonstrated that 392290-55-0, administered orally at 0.4 mg / kg / day for 7 days, produces an anticoagulant effect equivalent to warfarin. In vitro electrophysiological studies show that 392290-55-0, in hiPSC-CMs and isolated guinea pig hearts, concentration-dependently prolongs the action potential repolarization duration and effective refractory period, and also reduces atrial / ventricular ERP / APD. 90 The ratio remained >1.0 throughout, without inhibiting sinoatrial node automaticity, myocardial conduction function, or calcium homeostasis. These characteristics are consistent with the classic electrophysiological model of class III antiarrhythmic drugs. This dual pharmacological property effectively bridges the treatment gap between the anticoagulation requirements and rhythm control goals in patients with valvular atrial fibrillation, providing a novel integrated treatment strategy.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of a compound in the preparation of drugs for treating arrhythmias. Background Technology

[0002] Atrial fibrillation (AF) is the most common type of cardiac arrhythmia worldwide, and its disease burden continues to increase.

[0003] Rhythm control is one of the core strategies for the comprehensive management of atrial fibrillation. However, existing antiarrhythmic drugs (AADs) face serious safety challenges: amiodarone, while effective, is accompanied by multi-organ toxicity (thyroid dysfunction, pulmonary fibrosis, liver damage, etc.) and has a long half-life of 55–142 days; dronedarone has been shown in the PALLAS and ANDROMEDA trials to increase the risk of composite cardiovascular events (HR 2.29) and cardiovascular death (HR 2.11) in patients with moderate to severe heart failure (NYHA class III–IV); sotalol, according to a Cochrane meta-analysis, increases all-cause mortality (RR 2.23, 95% CI 1.03–4.81) and the risk of arrhythmia (RR 3.55, 95% CI 2.16–5.83). In the past decade, no breakthrough new drugs have been launched in the field of AADs, and clinical practice still mainly relies on traditional drugs such as amiodarone. Existing antiarrhythmic drugs (AADs) generally suffer from problems such as narrow therapeutic window, organ-specific toxicity, and arrhythmogenic potential, which contradict the need for long-term anticoagulation therapy in patients with atrial fibrillation. This highlights the urgent clinical need to develop novel pharmacological agents with both anticoagulant and antiarrhythmic effects. Summary of the Invention

[0004] In light of the aforementioned clinical challenges, this invention has discovered a compound (CAS: 392290-55-0) that exhibits dual pharmacological activities of vitamin K-dependent anticoagulation and myocardial electrophysiological regulation. Specifically, it inhibits vitamin K epoxide reductase (VKORC1), producing a stable, predictable, and reversible vitamin K-dependent anticoagulation effect. This ensures that in patients with valvular atrial fibrillation who are clearly contraindicated by DOACs (such as those with mechanical heart valves or moderate to severe mitral stenosis), it maintains stroke prevention value equivalent to warfarin. Simultaneously, its unique molecular structural modifications endow it with the ability to regulate voltage-gated potassium channels in myocardial cell membranes and stabilize atrial electrophysiology. This antiarrhythmic effect is significantly different from traditional warfarin and related vitamin K antagonists. Therefore, this dual-action characteristic offers a potential advantage in the management of atrial fibrillation patients requiring long-term anticoagulation therapy (especially those who must use warfarin due to valvular indications), potentially achieving both rhythm control and stroke prevention with a single treatment, reducing the treatment burden of multidrug therapy. The development of these compounds represents a major advance in the field of atrial fibrillation drug therapy, effectively bridging the treatment gap between anticoagulation requirements and rhythm control goals in the large patient population with valvular atrial fibrillation.

[0005] To achieve the above-mentioned objectives of this invention, the technical solution adopted by this invention is as follows: This invention provides the use of a compound in the preparation of a drug for treating arrhythmias and / or anticoagulation. The compound has the CAS number 392290-55-0 and its structural formula is shown in formula (I): Formula (I).

[0006] In some embodiments of the present invention, the arrhythmia includes atrial fibrillation.

[0007] In some embodiments of the present invention, the drug is a Class III antiarrhythmic drug.

[0008] In some embodiments of the present invention, antiarrhythmic drugs are classified into four classes according to their mechanism of action: Class I (sodium channel blockers), Class II (β-receptor blockers), Class III (potassium channel blockers), and Class IV (calcium channel blockers). The compounds of the present invention belong to Class III antiarrhythmic drugs (potassium channel blockers).

[0009] In some embodiments of the invention, the drug comprises a pharmaceutically acceptable salt.

[0010] In some embodiments of the present invention, the pharmaceutically acceptable salt includes an acid addition salt or a base addition salt.

[0011] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, are not undesirable in biological or other respects, and are formed from an inorganic acid and an organic acid, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and such as, but not limited to, acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor 10 sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, dodecyl sulfate, ethane 1,2 disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, fumaric acid, galactopyric acid, gentian acid, gluconic acid, glucuronic acid, glutamic acid, glutamate, 2-oxoglutamate, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, etc.

[0012] In some embodiments of the present invention, the medicament includes pharmaceutically acceptable excipients.

[0013] In some embodiments of the present invention, the pharmaceutically acceptable excipients include at least one of the following: solvents, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and anti-flocculators, filter aids, release inhibitors, and carriers.

[0014] The pharmaceutically acceptable excipients mentioned above are generally recognized for use in this purpose and as inactive ingredients in the pharmaceutical preparation. Compilations of pharmaceutically acceptable excipients can be found in reference books such as the *Handbook of Pharmaceutical Excipients* (2nd edition, edited by A. Wade and PJ Weller; published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994) and the *Pharmacopoeia of the People's Republic of China* (2020 edition, Volume IV, List of Pharmaceutical Excipients).

[0015] In some embodiments of the present invention, the dosage form of the drug includes a gastrointestinal dosage form or a non-gastrointestinal dosage form.

[0016] In some embodiments of the present invention, the gastrointestinal dosage form includes at least one of powder, tablet, granule, capsule, sustained-release, solution, dry suspension, effervescent tablet, emulsion, suspension, syrup, drops, and chewable tablet.

[0017] In some embodiments of the present invention, the non-gastrointestinal drug delivery dosage form includes at least one of injection dosage form, respiratory dosage form, skin dosage form, mucosal dosage form, and cavity dosage form.

[0018] In some embodiments of the present invention, the administration method of the drug includes oral, subcutaneous, intravenous, or intraperitoneal injection.

[0019] In some embodiments of the present invention, the drug is suitable for mammals.

[0020] In some embodiments of the present invention, the drug is applicable to humans.

[0021] In some embodiments of the invention, the medicament includes other active ingredients for treating arrhythmias.

[0022] The beneficial effects of this invention are: This invention provides the application of a compound (392290-55-0) possessing both vitamin K-dependent anticoagulant and myocardial electrophysiological regulatory activities in the preparation of anticoagulant and / or arrhythmia treatment drugs. In vivo animal experiments confirmed that 392290-55-0, administered orally at 0.4 mg / kg / day for 7 days, produced an anticoagulant effect equivalent to warfarin (no significant difference in INR levels), demonstrating therapeutic value in patients contraindicated by DOACs (mechanical heart valves, moderate to severe mitral stenosis). In vitro electrophysiological studies showed that 392290-55-0, in hiPSC-CMs and isolated guinea pig hearts, concentration-dependently prolonged action potential repolarization duration (APD). 90 and effective refractory period (ERP), and atrial / ventricular ERP / APD 90 The ratio remained >1.0 throughout, without inhibiting sinoatrial node automaticity, myocardial conduction function, or calcium homeostasis. These characteristics are consistent with the classic electrophysiological model of class III antiarrhythmic drugs, and their mechanism may involve the regulation of voltage-gated delayed rectifier potassium channels (I_Kr / I_Ks) on the myocardial cell membrane, rather than the inhibition of calcium or sodium channels. This "single molecule, dual target" pharmacological characteristic effectively bridges the treatment gap between the mandatory anticoagulation requirements and rhythm control goals in patients with valvular atrial fibrillation, providing a novel integrative treatment strategy for improving the long-term prognosis of this high-risk population. Attached Figure Description

[0023] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein: Figure 1 Toxicity assessment of 392290-55-0 against H9C2 (A) and its effect on coagulation function in mice (B).

[0024] Figure 2 The effect of 392290-55-0 on the electrophysiological properties of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs). A is a rhythm-corrected field potential duration (FPDcf) graph; B is a conduction velocity graph under 2Hz stimulation; C is a conduction dispersion graph under 2Hz stimulation; and D is a conduction thermogram (red represents the earliest excitation, and bluer represents slower conduction).

[0025] Figure 3 The results of the electrophysiological effects of 392290-55-0 on the ventricle are as follows: A is the statistical graph of ventricular action potential duration; B is the statistical graph of heart rate; C is the statistical graph of ventricular conduction velocity; D is the statistical graph of ventricular depolarization time; E is the statistical graph of ventricular action potential duration under a 4.5 Hz stimulation rhythm; F is the statistical graph of ventricular vERP duration under a 4.5 Hz stimulation rhythm; G is the statistical graph of ventricular vERP / APD under a 4.5 Hz stimulation rhythm; H is the waveform of ventricular calcium transient under a 4.5 Hz stimulation rhythm; I is the isochronous diagram of intracellular calcium conduction and the distribution of calcium transient duration under a 4.5 Hz stimulation rhythm.

[0026] Figure 4 The following graphs represent the electrophysiological effects of 392290-55-0 on the atria, where: A is the heart rate graph; B is the atrial conduction time graph; C is the atrial conduction velocity graph; D is the atrial action potential duration graph; E is the atrial calcium transient duration graph; FK are the statistical results under a 4.5Hz stimulation rhythm; F is the atrial conduction time graph; G is the atrial conduction velocity graph; H is the atrial action potential duration graph; I is the atrial effective refractory period graph; J is the atrial aERP / APD graph; and K is the atrial calcium transient duration graph. Detailed Implementation

[0027] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0028] The inventors previously tested the therapeutic potential of several candidate compounds. Compound 9 (CAS: 392290-55-0) showed potential antiarrhythmic effects, while compound 2 induced electrical alternation in the myocardium. Compounds 10 and 13 inhibited cardiomyocyte growth and exhibited potential toxicity. Therefore, this invention uses CAS: 392290-55-0 as the test drug. The compound (CAS: 392290-55-0) can be obtained through conventional commercial channels or synthesized using existing techniques.

[0029] Example 1: 392290-55-0 exhibits good anticoagulant activity. 1. Experimental Methods H9C2 rat cardiomyocytes were treated with 10 μM of the test drug (CAS: 392290-55-0, hereinafter referred to as 392290-55-0) for 48 hours, and the cell viability was detected by CCK-8 assay.

[0030] Male C57BL / 6 mice aged 8–10 weeks were randomly divided into two groups and administered warfarin sodium (0.4 mg / kg / day) or 392290-55-0 (0.4 mg / kg / day) by gavage, once every 24 hours, for 7 consecutive days. After the last administration, sodium citrate-anticoagulated whole blood was collected from the periorbital venous plexus, and prothrombin time (PT) was measured using a fully automated coagulation analyzer, and the international normalized ratio (INR) was calculated.

[0031] 2. Experimental Results The results indicated that 392290-55-0 had no inhibitory effect on cell growth and no significant cytotoxicity. Figure 1 (A)

[0032] No mice died during the administration period. INR test results showed no statistically significant difference in anticoagulant strength between the two groups ( Figure 1 (Middle B), indicating that the anticoagulant effect of 392290-55-0 is not inferior to that of the traditional anticoagulant warfarin.

[0033] Example 2: Evaluation of the effect of 392290-55-0 on the electrophysiological properties of hiPSC-CMs based on a microelectrode array system. 1. Experimental Methods Cell-free microelectrode arrays (MEAs) were immobilized on a multichannel cell mapping system. Cardiomyocyte culture medium was added, and the temperature control parameters were adjusted to maintain the MEA temperature at 36.5 ± 0.5 °C. MEAs containing hiPSC-CMs were then replaced. After signal stabilization for 5–10 minutes, field potential signals under spontaneous and stimulated rhythms were acquired using EMap Record software. Different concentrations of 392290-55-0 (100 nM and 10 μM) were added, with administration proceeding in ascending order of concentration for each experiment. Incubation was performed for 15 minutes at each concentration, and field potential signals under spontaneous and stimulated rhythms were recorded simultaneously. Each concentration was measured in triplicate.

[0034] 2. Experimental Results Figure 2 The results showed that 392290-55-0 significantly prolonged the field potential duration (FPDcf) corrected by the Bazett formula under spontaneous rhythms of hiPSC-CMs, slowed the conduction velocity (CV) under stimulus rhythms, and increased the conduction dispersion under stimulus rhythms. Moreover, this effect was reversible and could be restored to the baseline level after washing.

[0035] Example 3: Evaluation of the electrophysiological effects of Langendorff perfusion on the ventricles of isolated guinea pig hearts (392290-55-0). 1. Experimental Methods Healthy adult guinea pigs were euthanized by cervical dislocation after intraperitoneal injection of heparin sodium for anticoagulation. The heart was quickly removed via thoracotomy and placed in Krebs-Henseleit (KH) solution. After aortic dissection, modified Langendorff retrograde perfusion was performed. Once the heart regained a stable sinus rhythm, Blebbistatin was added to the circulating KH solution to eliminate mechanical contraction artifacts. Pluronic F-127 was used to assist in loading the calcium-sensitive dye Rhod-2 AM and the voltage-sensitive dye RH237. The heart was then moved to an imaging perfusion chamber, where epicardial voltage and calcium transient signals were simultaneously acquired using a dual CMOS camera (OMS-PCIE-2002, MappingLab, 0.8 kHz sampling rate). A bipolar platinum electrode was inserted at the apex of the heart, and myocardial electrophysiological characteristics were assessed using S1S1 (4.5 Hz) and S1S2 programmed stimulation; the pacing current was set to twice the diastolic threshold. Offline analysis was performed using OMapScope 5.7.8 software. After 3×3 pixel Gaussian spatial filtering, the activation time (AT) was determined and the conduction velocity (CV) was calculated. The action potential repolarization time history (APD) was defined as the time from repolarization to 90% of the baseline. 90 The calcium transient time history (CaTD) is defined as the recovery of calcium transients to 90% of their peak value. 90 ).

[0036] 2. Experimental Results like Figure 3 As shown in Figures A–D, under spontaneous sinus rhythm conditions, 392290-55-0 prolongs ventricular myocardial apoplexy (APD) within a concentration range of 1 nM–1 μM. 90 ( Figure 3 (A), while for baseline sinus heart rate ( Figure 3 (B) Ventricular conduction velocity (CV) Figure 3 (C) and depolarization time (Rise Time) Figure 3 There was no significant effect on either the middle or lower ventricular automaticity (D). These results suggest that 392290-55-0 has no significant inhibitory effect on sinoatrial node automaticity, gap junction conduction between cardiomyocytes, or fast sodium channel activity. Under 4.5 Hz exogenous pacing, 392290-55-0 synchronously prolongs ventricular atrial prolongation (APD). 90 ( Figure 3 (E) and effective refractory period (vERP) Figure 3 (in the middle F), and the vERP / APD ratio of each concentration group 90 The ratio remains constant. Figure 3 (No significant difference was observed in G). According to basic electrophysiological principles, the physiological matching of ERP and APD is crucial for maintaining myocardial electrical stability; if a drug selectively prolongs APD without correspondingly prolonging ERP, cardiomyocytes will regain excitability before repolarization is complete, easily inducing early afterdepolarization (EADs) and reentrant arrhythmias. In this study, ERP and APD... 90 The synchronous extension, and vERP / APD 90 The ratio did not change significantly, indicating that within the detection concentration range, 392290-55-0 does not increase the arrhythmogenic potential.

[0037] like Figure 3 As shown in H and I, the isochrones of calcium activation time show that the calcium activation conduction mode and conduction sequence are basically the same across concentration groups; the calcium transient time-transition (CaTD) isochrones also show this. 90 The heatmap showed that all groups were uniformly dark blue (high value area), and there were no significant differences between concentrations. Quantitative analysis indicated that 392290-55-0 had an effect on ventricular calcium wave conduction velocity and CaTD. 90 There was no significant impact (consistent with the CV results obtained from voltage calibration).

[0038] Based on the fundamental principles of cardiomyocyte electrophysiology, the action potential repolarization process is primarily regulated by the plateau-phase inward current mediated by voltage-gated L-type calcium channels (I_Ca,L) and the outward repolarization current mediated by various voltage-gated potassium channels. Given that 392290-55-0 significantly prolongs APD... 90 At the same time: ① the calcium transient kinetic parameters (CaTD) remain unchanged. 90 No change Figure 3I) Excluding abnormal sarcoplasmic reticulum calcium release / reuptake mechanisms; ② No change in depolarization time (Rise Time showed no significant change). Figure 3 (D), excluding the significant inhibitory effect of fast sodium channels. Based on this, it can be reasonably inferred that the electrophysiological effect of 392290-55-0 in prolonging myocardial repolarization may be achieved by regulating the voltage-gated potassium channels of ventricular myocyte membranes (especially the delayed rectifier potassium channels I_Kr and / or I_Ks involved in phase III repolarization).

[0039] Example 4: Evaluation of the electrophysiological effects of Langendorff perfusion on the atria of isolated guinea pig hearts (392290-55-0). 1. Experimental Methods In a Langendorff perfusion model of isolated guinea pig hearts, the effects of 392290-55-0 on atrial electrophysiological properties were systematically evaluated using optical mapping techniques. The procedures were the same as in Example 3.

[0040] 2. Experimental Results The results showed that, under spontaneous sinus rhythm conditions, 392290-55-0 significantly prolonged the atrial action potential repolarization duration (APD) within the concentration range of 1 nM–10 μM. 90 , Figure 4 (Middle D), but for baseline sinus heart rate ( Figure 4 (A) Atrial conduction time ( Figure 4 (B) and atrial conduction velocity ( Figure 4 Neither C nor D had a significant effect. Under 4.5 Hz programmed electrical stimulation, the 392290-55-0 synchronous stimulation significantly prolonged atrial APD. 90 ( Figure 4 (H) and effective refractory period (aERP, Figure 4 (I), and each concentration group aERP / APD 90 The ratio remains constant. Figure 4 (No significant difference in J). Under spontaneous sinus rhythm, 392290-55-0 was associated with atrial calcium transient duration (CaTD). 90 No significant effect () Figure 4 (E). Under 4.5 Hz high-frequency pacing conditions, CaTD appeared at certain concentration points. 90 Mild shortening ( Figure 4 (medium K), but this change lacked concentration dependence (the 10 μM group recovered to the control level), and was related to APD. 90 The significant extension (>70%) was disproportionate.

[0041] The above characteristics suggest that 392290-55-0 has no direct pharmacological effect on atrial myocardial calcium homeostasis; CaTD at 4.5 Hz 90The slight fluctuations in cardiac activity may stem from physiological frequency-dependent adaptations to sarcoplasmic reticulum calcium processing under high-frequency pacing, or from a redistribution of the calcium efflux time window following prolonged action potentials, rather than direct inhibition of calcium channels or calcium processing proteins by the drug. Therefore, the primary mechanism by which 392290-55-0 prolongs atrial repolarization time still points to regulation by voltage-gated potassium channels (I_Kr / I_Ks). In vitro optical mapping studies have shown that 392290-55-0, by prolonging the myocardial effective refractory period and action potential repolarization time while maintaining an ERP / APD ratio >1.0, exhibits typical electrophysiological characteristics of a class III antiarrhythmic drug, providing sufficient pharmacological evidence for subsequent in vivo verification of its antiarrhythmic activity.

[0042] The embodiments of the present invention have been described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the above embodiments, and various changes can be made within the scope of knowledge possessed by those skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. Application of the compound in the preparation of drugs for treating arrhythmias; The structural formula of the compound is shown in formula (I): Equation (Ⅰ).

2. The application according to claim 1, characterized in that: The arrhythmia mentioned includes atrial fibrillation.

3. The application according to claim 1, characterized in that: The drug in question is a Class III antiarrhythmic drug.

4. The application according to claim 1, characterized in that: The drug includes pharmaceutically acceptable salts.

5. The application according to claim 1, characterized in that: The drug includes pharmaceutically acceptable excipients.

6. The application according to claim 5, characterized in that: Pharmaceutically acceptable excipients include carriers.

7. The application according to claim 6, characterized in that: The dosage forms of the drug include those administered via the gastrointestinal tract or those administered outside the gastrointestinal tract.

8. The application according to claim 6, characterized in that: The drug can be administered orally, subcutaneously, intravenously, or intraperitoneally.

9. The application according to claim 6, characterized in that: The drug is suitable for mammals.

10. The application according to any one of claims 5 to 9, characterized in that: The drug includes other active ingredients for treating arrhythmias.

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