BRL-32872

Last updated
BRL-32872
BRL-32872.svg
Names
Preferred IUPAC name
N-(3,4-Dimethoxyphenyl)-N-(3-{[2-(3,4-dimethoxyphenyl)ethyl]methylamino}propyl)-4-nitrobenzamide
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=1S/C29H35N3O7/c1-30(18-15-21-7-13-25(36-2)27(19-21)38-4)16-6-17-31(24-12-14-26(37-3)28(20-24)39-5)29(33)22-8-10-23(11-9-22)32(34)35/h7-14,19-20H,6,15-18H2,1-5H3 Yes check.svgY
    Key: ADAGRLDCCJAKFP-UHFFFAOYSA-N Yes check.svgY
  • InChI=1S/C29H35N3O7/c1-30(18-15-21-7-13-25(36-2)27(19-21)38-4)16-6-17-31(24-12-14-26(37-3)28(20-24)39-5)29(33)22-8-10-23(11-9-22)32(34)35/h7-14,19-20H,6,15-18H2,1-5H3
  • [O-][N+](=O)c1ccc(cc1)C(=O)N(c2cc(OC)c(OC)cc2)CCCN(CCc3ccc(OC)c(OC)c3)C
Properties
C29H35N3O7
Molar mass 537.613 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

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. [1]

Contents

Arrhythmia

Cardiac arrhythmia arises from abnormalities in action potential formation and propagation through the heart. Changes in electrolyte balance, or development of ectopic pacemaker activity, disrupt normal heart rhythmicity and conduction. [2] Antiarrhythmic agents are used to manipulate ion flux through membrane channels to restore normal pacemaker activity. Cellular conduction and refractory periods are also modified to eliminate re-entry depolarization causing arrhythmia. Factors contributing to the generation of arrhythmia include: ischemia, hypoxia, acidosis and drug toxicity. If untreated, arrhythmias may present as bradycardia, tachycardia, or progress to atrial/ventricular fibrillation. [3]

Class III activity

BRL-32872’s class III activity is directed towards the human ether-a-go-go-related gene (hERG) K+ channel. [4] hERG channels are the source of the delayed rectifier potassium current (IK); the current responsible for repolarization of the cardiac action potential. BRL-32872 binds with high affinity to open hERG channels, and inhibits the rapidly activating component of the IK. [4] BRL-32872 binding effectively increases the refractory period of the cell and prolongs the action potential. This blockage also reduces probability of re-entry depolarization, since signals are more likely to encounter tissue in a refractory state. This effect is particularly well suited for treating atrial and ventricular fibrillation, as it restores pacemaker control of the tissue to the SA and AV nodes. [3] The specific binding site of BRL-32872 on the hERG channel is unknown; evidence suggests however, that it lies within the channels pore, similar to other class III drugs. [4]

Class IV activity

BRL-32872’s class IV activity is similar to that of its parent drug, verapamil. The drug targets L-type Ca+2 channels, and decreases conduction in cells where Ca+2 is required for action potential upstroke (SA/AV nodes). [5] The result is increased nodal conduction time and refractoriness, restoring normal heart rate in patients with tachycardia. Binding occurs on the pore-forming α1 subunit during the open or inactive state. [6] This low level of ICa inhibition is credited with eliminating some of the proarrhythmial effects of class III drugs. The combined inhibition of K+/Ca+2 channels has proven to eliminate the occurrence of early after-depolarizations (EAD’s), in comparison to selective class III agents alone. [7]

Benefits of BRL-32872

Unlike most antiarrhythmics, BRL-32872’s effects are homogeneous within the various cardiac tissue types (nodal cells, cardiomyocytes, Purkinje fibers). [7] This property helps eliminate repolarization dispersion, a proarrhythmial effect noted in class III agents. BRL-32872 does not exhibit reverse-use dependence; meaning efficacy is conserved regardless of heart rate. [7] The drug is also easily administered orally or via intravenous injection, and has no effect on resting membrane potential. [5] The effects BRL-32872 have been well documented in animal models. However, its effect has not yet been demonstrated in humans.  These beneficial experimental results make a strong case for the use of drugs such as BRL-32872, with combined K+/Ca+2 inhibition, in first line antiarrhythmial treatment.

Related Research Articles

Cardioversion

Cardioversion is a medical procedure by which an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia is converted to a normal rhythm using electricity or drugs. Synchronized electrical cardioversion uses a therapeutic dose of electric current to the heart at a specific moment in the cardiac cycle, restoring the activity of the electrical conduction system of the heart. Pharmacologic cardioversion, also called chemical cardioversion, uses antiarrhythmia medication instead of an electrical shock.

Antiarrhythmic agent

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart, such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation.

Dofetilide Antiarrhythmic medication

Dofetilide is a class III antiarrhythmic agent. It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 µg of dofetilide. It is not available in Europe or Australia. In the United States it is only available by mail order or through specially trained local pharmacies.

Torsades de pointes Type of abnormal heart rhythm

Torsades de pointes, torsade de pointes or torsades des pointes (TdP) 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%-10% of patients who receive QT-prolonging antiarrhythmic drugs.

The cardiac action potential is a brief change in voltage across the cell membrane of heart cells. This is caused by the movement of charged atoms between the inside and outside of the cell, through proteins called ion channels. The cardiac action potential differs from action potentials found in other types of electrically excitable cells, such as nerves. Action potentials also vary within the heart; this is due to the presence of different ion channels in different cells.

Procainamide

Procainamide is a medication of the antiarrhythmic class used for the treatment of cardiac arrhythmias. It is classified by the Vaughan Williams classification system as class Ia; thus it is a sodium channel blocker of cardiomyocytes. In addition to blocking the INa current, it inhibits the IKr rectifier K+ current. Procainamide is also known to induce a voltage-dependent open channel block on the batrachotoxin (BTX)-activated sodium channels in cardiomyocytes.

Azimilide

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.

Disopyramide

Disopyramide is an antiarrhythmic medication used in the treatment of ventricular tachycardia. It is a sodium channel blocker and therefore classified as a Class 1a anti-arrhythmic agent. Disopyramide has a negative inotropic effect on the ventricular myocardium, significantly decreasing the contractility. Disopyramide also has an anticholinergic effect on the heart which accounts for many adverse side effects. Disopyramide is available in both oral and intravenous forms, and has a low degree of toxicity.

Ajmaline

Ajmaline is an alkaloid that is classified as a 1-A antiarrhythmic agent. It is often used to induce arrhythmic contraction in patients suspected of having Brugada syndrome. Individuals suffering from Brugada syndrome will be more susceptible to the arrhythmogenic effects of the drug, and this can be observed on an electrocardiogram as an ST elevation.

Lorcainide

Lorcainide is a Class 1c antiarrhythmic agent that is used to help restore normal heart rhythm and conduction in patients with premature ventricular contractions, ventricular tachycardiac and Wolff-Parkinson-White syndrome. Lorcainide was developed by Janssen Pharmaceutica (Belgium) in 1968 under the commercial name Remivox and is designated by code numbers R-15889 or Ro 13-1042/001. It has a half-life of 8.9 +- 2.3 hrs which may be prolonged to 66 hrs in people with cardiac disease.

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.

Pilsicainide

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.

Potassium channel blocker Several medications that disrupt movement of K+ ions

Potassium channel blockers are agents which interfere with conduction through potassium channels.

E-4031

E-4031 is an experimental class III antiarrhythmic drug that blocks potassium channels of the hERG-type.

Celivarone Experimental drug being tested for use in pharmacological antiarrhythmic therapy

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.

Budiodarone

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.

AZD1305 Chemical compound

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).

HBI-3000 Chemical compound

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

XEN-D0101 is an experimental drug that was developed to treat atrial fibrillation. Xention, a biopharmaceutical company based in Cambridge, United Kingdom, 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.

References

  1. ↑ Nadler, G., Faivre, J. F., Forest, M. C., Cheval, B., Martin, M., Souchet, M., et al. (1998). Synthesis, electrophysiological properties and analysis of structural requirements of a novel class of antiarrhythmic agents with potassium and calcium channel blocking properties. Bioorganic & Medicinal Chemistry, 6(11), 1993-2011
  2. ↑ Guyton, Arthur C., Hall, John E. (2006). Textbook of Medical Physiology (11th ed.). Philadelphia: Elsevier Saunders. ISBN   0-7216-0240-1
  3. 1 2 Katzung, Bertram G.; Masters, Susan B.; Trevor, Anthony J. (2009). Basic and Clinical Pharmacology. 11th ed. New York: McGraw Hill. ISBN   978-0-07-160405-5
  4. 1 2 3 Thomas, D., Wendt-Nordahl, G., Rockl, K., Ficker, E., Brown, A. M., & Kiehn, J. (2001). High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872. The Journal of Pharmacology and Experimental Therapeutics, 297(2), 753-761.
  5. 1 2 Bril, A., Faivre, J. F., Forest, M. C., Cheval, B., Gout, B., Linee, P., et al. (1995). Electrophysiological effect of BRL-32872, a novel antiarrhythmic agent with potassium and calcium channel blocking properties, in guinea pig cardiac isolated preparations. The Journal of Pharmacology and Experimental Therapeutics, 273(3), 1264-1272
  6. ↑ Cheng, R. C., Tikhonov, D. B., & Zhorov, B. S. (2009). Structural model for phenylalkylamine binding to L-type calcium channels. The Journal of Biological Chemistry, 284(41), 28332-28342
  7. 1 2 3 Faivre, J. F., Forest, M. C., Gout, B., & Bril, A. (1999). Electrophysiological characterization of BRL-32872 in canine purkinje fiber and ventricular muscle: Effect on early after-depolarizations and repolarization dispersion. European Journal of Pharmacology, 383(2), 215-222
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