SUMMARY
UCLA researchers in the Department of Chemistry & Biochemistry have developed novel small molecule compounds for alleviating cardiac arrhythmia. These new compounds are analogs of existing anti-arrhythmic molecule, efsevin, demonstrating enhanced anti-arrhythmic activity compared to efsevin.
BACKGROUND
Cardiac arrhythmias are responsible for more than half of all cardiovascular deaths. Regular heart rhythms are maintained by changes in the concentration of calcium ions (Ca+) in the cytoplasm of the heart muscle cells. Inability to efficiently regulate the movement of Ca+ from cytoplasm leads to irregular heart rhythms. Current anti-arrhythmic drugs are associated with major side effects. They target cell membrane receptors and channels to help restore regular heart rhythms; however, they do not modulate defective intracellular Ca+ signaling that is primarily responsible for causing cardiac arrhythmias.
Recently, Voltage-dependent anion channel 2 (VDAC2), has been found to play a critical role in Ca+ transportation between cytoplasm and mitochondria within the heart muscle cells making it potential therapeutic target against cardiac arrhythmias. Efsevin, a novel small molecule compound has recently been identified to bind to VDAC2 and restore rhythmic Ca+ cycling. However, efsevin has limited metabolic stability and/or bioavailability profile in vivo making it critical to develop efsevin analogs that demonstrate increased metabolic stability, bioavailability and enhanced activity,
INNOVATION
Dr. Ohyun Kwon and colleagues in the Department of Chemistry & Biochemistry at UCLA have developed new small molecule analogs of efsevin. These novel efsevin analogs serve as attractive anti-arrhythmic drug candidates since they demonstrated increased modulation of intracellular Ca+ homeostasis,
APPLICATION
- Ca+ triggered cardiac arrhythmias
- Regulation of heart rhythms
- Calcium ion transportation
ADVANTAGES
- Enhanced potency in anti-arrhythmic activity
- Enhanced binding activity to VDAC2
- Low side-effects
STATE OF DEVELOPMENT
Analogs of efsevin have been synthesized and tested in zebrafish model. Further testing is needed.
RELATED PAPERS
Patent application publication: US20170362173A1 (Worldwide applications: WO, PCT/US2015/065876; US15/536,314; EP15870900.6A)