Rsd 1070

HO RSD 1235

the pKa was ~6.5 (i.e., the pH in ischemic myocardial tissue). With regard to site C an ester at this position was useful but, not unexpectedly, gave only a short duration of action. However an ether substitution was suitable and provided useful compounds. Further modifications provided compounds with better pharmacokinetic profiles and lesser toxicity. Thus, using classic SAR it proved possible to make compounds whose potency was increased at acid pH values ( e 6.5). Patch clamp studies suggested an extracellular site of action as well as positive frequency (inactivation) dependency. When tested in vivo against ischemia induced arrhythmias in anesthetized rats, the best compounds selectively protected against the arrhythmias induced by ischemia versus those induced by electrical stimulation in normal cardiac tissue. Further studies showed that they also blocked potassium channels.

As indicated above a basic part of the approach was to make compounds with a pKa of around 6.5, close to the pH found in ischemic tissue at the time when arrhythmias occur. This involved identifying the ring nitrogen that was essential for channel blockade and ascertaining that the pKa of this nitrogen could be manipulated by substitution on, or next to, the ring. The second amide nitrogen in RSD921 played no role since it could be replaced by an ester-, or ether-oxygen without loss of activity. In those compounds which provided 100% protection against ischemia induced arrhythmias the pKa of the ring nitrogen was around 6.5.50

Various studies have shown that in normal cardiac tissue, a moderately elevated [K+ ]o (4-7 mM) is antiarrhythmic, but how important is such a mechanism in ischemic tissue? The effects of increased [K+ ]o were therefore studied and raised potassium was found to add to the effects of acidity. Thus RSD1000 (Figure 10) was more than 10 times more potent than reference class 1 antiarrhythmics against ischemia induced arrhythmias.46 Related morpholinocyclohexyls, including RSD1019 (Figure 10) and RSD1030, showed a similar increased efficacy with a combination of high [K+ ]o and low pH, and all compounds had favorable therapeutic ratios versus the standard antiarrhythmic reference drugs.

The result of these studies were compounds that were reasonably potent, effective, and selective against ischemia induced arrhythmias in rats and pigs while having a satisfactory therapeutic ratios (compared with other antiarrhythmics) in terms of cardiovascular and CNS toxicity.

Compounds in the above series were also recognized as being potentially useful in the treatment of atrial arrhythmias in that, besides blocking sodium channels with a frequency dependent action, they also blocked IKto and IKur potassium channels. Such actions resulted in atrial selectivity. In atrial fibrillation, blood flow through the fibrillating atria is compromised, and thus a condition of partial ischemia prevails. All these characteristics resulted in compounds in which further manipulations improved pharmacokinetic properties and finally resulted in RSD1235. This compound has been found effective in phase III clinical trials in terminating acute-onset atrial fibrillation when injected intravenously.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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