AZD1305

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]

AZD1305
Names
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
UNII
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).
Infobox references

Pathology

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]

Mechanism

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]

Benefits

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]

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References
  1. Sicouri, S.; Carlsson, L.; Antzelevitch, C. (2010). "Electrophysiologic and Antiarrhythmic Effects of AZD1305 in Canine Pulmonary Vein Sleeves". Journal of Pharmacology and Experimental Therapeutics. 334 (1): 255–9. doi:10.1124/jpet.110.166702. PMC 2912040. PMID 20360353.
  2. Guyton, Arthur C., Hall, John E. (2006). Textbook of Medical Physiology (11th ed.). Philadelphia: Elsevier Saunders
  3. Kang, S. (2011). Atrial fibrillation. In A.D.A.M. Medical Encyclopedia. Retrieved from https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001236/
  4. Carlsson, Leif; Andersson, Birgit; Linhardt, Gunilla; Löfberg, Lena (2009). "Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit in Vivo". Journal of Cardiovascular Pharmacology. 54 (1): 82–9. doi:10.1097/FJC.0b013e3181ac62c9. PMID 19528812.
  5. Andersson, B; Abi-Gerges, N; Carlsson, L (2010). "The combined ion channel blocker azd1305 attenuates late Na current and IKr-induced action potential prolongation and repolarization instability". Europace. 12: 1003–10. doi:10.1093/europace/euq070.
  6. Sanguinetti, Michael C.; Tristani-Firouzi, Martin (2006). "HERG potassium channels and cardiac arrhythmia". Nature. 440 (7083): 463–9. doi:10.1038/nature04710. PMID 16554806.
  7. Burashnikov, Alexander; Zygmunt, Andrew C; Di Diego, Jose M; Linhardt, Gunilla; Carlsson, Leif; Antzelevitch, Charles (2010). "AZD1305 Exerts Atrial Predominant Electrophysiological Actions and is Effective in Suppressing Atrial Fibrillation and Preventing Its Reinduction in the Dog". Journal of Cardiovascular Pharmacology. 56 (1): 80–90. doi:10.1097/FJC.0b013e3181e0bc6b. PMC 2905470. PMID 20386458.
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