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Names | |
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IUPAC name 2-Methyl-2-propanyl (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)carbamate | |
Identifiers | |
3D model (JSmol) | |
ChemSpider | |
ECHA InfoCard | 100.170.290 |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C22H31FN4O4 | |
Molar mass | 434.512 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
AZD1305 is an experimental drug candidate that is under investigation for the management and reversal of cardiac arrhythmias, specifically atrial fibrillation and flutter. In vitro studies have shown that this combined-ion channel blocker inhibits rapidly the activating delayed-rectifier potassium current (IKr), L-type calcium current, and inward sodium current (INa). [1]
Atrial fibrillation (AF) is a form of cardiac arrhythmia that arises with disorganized and rapid action upotentials conducted through the atria, resulting in irregular atrial contraction. [2] Causes of AF include hypertension, cardiomyopathies, alcohol consumption, viral infections, and sleep apnea, which can cause AF by increasing the occurrence of early after depolarizations (EADs). [3] EAD is an abnormal depolarization and increase in action potential frequency that occurs in cardiac myocytes before normal repolarization is complete. [4] [5]
AZD1305 possesses class III anti-arrhythmic activity by blocking the human ether-a-go-go-related gene (hERG) potassium channel. [4] hERG contributes to the formation of potassium ion channel proteins that are responsible for the conduction of the rapid delayed rectifying potassium current. [6] Blocking this current prolongs action potential duration (APD), increases refractory period, and delays repolarization of cardiac myocytes in the ventricles and atria. [4] Delayed repolarizations increase susceptibility to EAD.
AZD 1305 also acts on voltage gated sodium channels (Nav1.5) by attenuating the peak (INapeak) and late sodium current (INalate), though the latter current is more potently inhibited. [5] Attenuation of INalate by AZD1305 is concentration-dependent and decreases the slope of depolarization and delays repolarization. INalate blockade by AZD1305 depressed the threshold of sodium channel excitation and prolongs APD. [7] Blockade of IKr may lead to excessive prolongation of APD and repolarization instability, which may promote arrhythmic conditions in the heart, including EAD and Torsade de Pointes (TdP). [5] Under IKr blockade a pronounced INalate can contribute to the development of arrhythmias by increasing repolarization variability. AZD1305 blockade of the INalate modulates IKr-blockade induced APD instability, repolarization vulnerability, and variability in beat-to-beat APD. [4] [5]
In vivo, as well as in vitro studies discovered that inhibition of INa and IKr by AZD1305 is much greater in atrial versus ventricular myocytes. [1] [7] This atrial-selective activity of AZD1305 prolongs effective refractory period (ERF) and induces post-repolarization refractoriness (PRR) in atrial myocytes, which aids in suppressing atrial fibrillation. [7]
AF and TdP may be induced with L-type calcium channel hyperactivity and increased calcium release from the sarcoplasmic reticulum. The L-type calcium current is also blocked by AZD 1305 which suppresses the intracellular rises in calcium levels and calcium oscillations that produce EADs. [1] [4] The combined block of INa, IKr, and L-type calcium current is key to the anti-arrhythmic potential of AZD1305 compared IKr blockade alone. [1]
Available anti-arrhythmic agents (AAD) used for the maintenance of AF are often accompanied with the risk of developing ventricular pro-arrhythmias, as they are often limited to targeting a single ion channel (i.e., Dofeiltide) and have homogenous activity throughout the heart. [4] AZD1305 offers the advantage of being an atrial-selective AAD and combined ion channel blocker that provides protection against EAD, repolarization dispersion, and ventricular pro-arrythmias. [1] [4] [7] Simultaneously, AZD1305 suppresses AF in a safe and efficacious manner, which could potentially be an ideal first-line treatment option in the future. [1]
The contraction of cardiac muscle in all animals is initiated by electrical impulses known as action potentials that in the heart are known as cardiac action potentials. The rate at which these impulses fire controls the rate of cardiac contraction, that is, the heart rate. The cells that create these rhythmic impulses, setting the pace for blood pumping, are called pacemaker cells, and they directly control the heart rate. They make up the cardiac pacemaker, that is, the natural pacemaker of the heart. In most humans, the highest concentration of pacemaker cells is in the sinoatrial (SA) node, the natural and primary pacemaker, and the resultant rhythm is a sinus rhythm.
Refractoriness is the fundamental property of any object of autowave nature not responding to stimuli, if the object stays in the specific refractory state. In common sense, refractory period is the characteristic recovery time, a period that is associated with the motion of the image point on the left branch of the isocline .
In electrocardiography, the ventricular cardiomyocyte membrane potential is about −90 mV at rest, which is close to the potassium reversal potential. When an action potential is generated, the membrane potential rises above this level in five distinct phases.
Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.
Torsades de pointes, torsade de pointes or torsades des pointes is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG). It was described by French physician François Dessertenne in 1966. Prolongation of the QT interval can increase a person's risk of developing this abnormal heart rhythm, occurring in between 1% and 10% of patients who receive QT-prolonging antiarrhythmic drugs.
Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by nervous activity. Instead, it arises from a group of specialized cells known as pacemaker cells, that have automatic action potential generation capability. In healthy hearts, these cells form the cardiac pacemaker and are found in the sinoatrial node in the right atrium. They produce roughly 60–100 action potentials every minute. The action potential passes along the cell membrane causing the cell to contract, therefore the activity of the sinoatrial node results in a resting heart rate of roughly 60–100 beats per minute. All cardiac muscle cells are electrically linked to one another, by intercalated discs which allow the action potential to pass from one cell to the next. This means that all atrial cells can contract together, and then all ventricular cells.
In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarization phase usually returns the membrane potential back to the resting membrane potential. The efflux of potassium (K+) ions results in the falling phase of an action potential. The ions pass through the selectivity filter of the K+ channel pore.
Azimilide is a class ΙΙΙ antiarrhythmic drug. The agents from this heterogeneous group have an effect on the repolarization, they prolong the duration of the action potential and the refractory period. Also they slow down the spontaneous discharge frequency of automatic pacemakers by depressing the slope of diastolic depolarization. They shift the threshold towards zero or hyperpolarize the membrane potential. Although each agent has its own properties and will have thus a different function.
In electrocardiography, during a cardiac cycle, once an action potential is initiated, there is a period of time that a new action potential cannot be initiated. This is termed the effective refractory period (ERP) of the tissue. This period is approximately equal to the absolute refractory period (ARP), it occurs because the fast sodium channels remain closed until the cell fully repolarizes. During this period, depolarization on adjacent cardiac muscles does not produce a new depolarization in the current cell as it has to refract back to phase 4 of the action potential before a new action potential can activate it. ERP acts as a protective mechanism and keeps the heart rate in check and prevents arrhythmias, and it helps coordinates muscle contraction. Anti-arrhythmic agents used for arrhythmias usually prolong the ERP. For the treatment of atrial fibrillation, it is a problem that the prolongation of the ERP by these agents also affects the ventricles, which can induce other types of arrhythmias.
Afterdepolarizations are abnormal depolarizations of cardiac myocytes that interrupt phase 2, phase 3, or phase 4 of the cardiac action potential in the electrical conduction system of the heart. Afterdepolarizations may lead to cardiac arrhythmias. Afterdepolarization is commonly a consequence of myocardial infarction, cardiac hypertrophy, or heart failure. It may also result from congenital mutations associated with calcium channels and sequestration.
Tedisamil (3,7-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo-3,3,1-nonane) is an experimental class III antiarrhythmic agent currently being investigated for the treatment of atrial fibrillation. Tedisamil blocks multiple types of potassium channels in the heart resulting in slowed heart rate. While the effects of tedisamil have been demonstrated in both atrial and ventricular muscle, repolarization is prolonged more efficiently in the atria. Tedisamil is administered intravenously and has a half-life of approximately 8 –13 hours in circulation. Tedisamil is being developed as an alternative to other antiarrhythmics as incidence of additional arrhythmic events is lower compared to other class III agents. Tedisamil also has significant anti-ischemic properties and was initially investigated as a potential treatment for angina until its antiarrhythmic effects were discovered. Tedisamil is manufactured by Solvay Pharmaceuticals Inc. under the proposed trade name Pulzium.
Pilsicainide (INN) is an antiarrhythmic agent. It is marketed in Japan as サンリズム (Sunrythm). It was developed by Suntory Holdings Limited and first released in 1991. The JAN applies to the hydrochloride salt, pilsicainide hydrochloride.
Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels.
BRL-32872 is an experimental drug candidate that provides a novel approach to the treatment of cardiac arrhythmia. Being a derivative of verapamil, it possesses the ability to inhibit Ca+2 membrane channels. Specific modifications in hydrogen bonding activity, nitrogen lone pair availability, and molecular flexibility allow BRL-32872 to inhibit K+ channels as well. As such, BRL-32872 is classified as both a class III (K+ blocking) and class IV (Ca+2 blocking) antiarrhythmic agent.
Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.
N-(p-Amylcinnamoyl)anthranilic acid (ACA) is a modulator of various ion channels in the heart. ACA is an effective reversible inhibitor of calcium-activated chloride channels and, to a lesser extent, cAMP-activated chloride channels, without affecting L-type calcium channels. Calcium-activated chloride channels are believed to be involved in developing arrhythmia.
Budiodarone (ATI-2042) is an antiarrhythmic agent and chemical analog of amiodarone that is currently being studied in clinical trials. Amiodarone is considered the most effective antiarrhythmic drug available, but its adverse side effects, including hepatic, pulmonary and thyroid toxicity as well as multiple drug interactions, are discouraging its use. Budiodarone only differs in structure from amiodarone through the presence of a sec-butyl acetate side chain at position 2 of the benzofuran moiety. This side chain allows for budiodarone to have a shorter half-life in the body than amiodarone which allows it to have a faster onset of action and metabolism while still maintaining similar electrophysiological activity. The faster metabolism of budiodarone allows for fewer adverse side effects than amiodarone principally due to decreased levels of toxicity in the body.
HBI-3000 is an experimental drug candidate that is currently in phase II of human clinical trials as an antiarrhythmic agent. Clinical investigation will test the safety and efficacy of HBI-3000 as a treatment for both atrial and ventricular arrhythmias.
XEN-D0101 is an experimental drug that was developed to treat atrial fibrillation. Xention, a biopharmaceutical company based in Cambridge, England, created XEN-D0101 along with other ion channel-modulating drugs. XEN-D0101 is a selective antagonist of the voltage-gated potassium channel Kv1.5. Atrial fibrillation is the main focus of Xention’s drug development, as it is the most common cardiac arrhythmia seen in patients.
QT prolongation is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between beats. It is an electrical disturbance which can be seen on an electrocardiogram (ECG). Excessive QT prolongation can trigger tachycardias such as torsades de pointes (TdP). QT prolongation is an established side effect of antiarrhythmics, but can also be caused by a wide range of non-cardiac medicines, including antibiotics, antidepressants, antihistamines, opioids, and complementary medicines. On an ECG, the QT interval represents the summation of action potentials in cardiac muscle cells, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, resulting in QT prolongation.