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BRL-32872
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] ArrhythmiaCardiac 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 activityBRL-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 activityBRL-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-32872Unlike 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. References
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