An antipsychotic with no HERG liability was discovered. The compound did not cause action potential duration increases when tested in Purkinje fibers and paced anesthetized dogs. Since dopamine antagonism was part of the mechanism of action, the compound did retain a potent alpha-adrenergic blocking activity in the anticipated therapeutic concentration range. Oral (to cover any potential metabolites) and intravenous evaluation of the compound in the conscious dog produced acute lowering of blood pressure with concomitant increases in heart rate (reflex tachycardia) in the therapeutic range. Analyses of beat-to-beat QT-RR interval relationship during hypotension and reflex tachycardia showed that in 100% of the dogs the QT interval did not exceed the upper 95% confidence bounds of the baseline relationship. However, these same beats when corrected with Bazett or Fridericia functions were significantly prolonged compared to baseline. Conscious dog and monkey studies conducted in Toxicology using corrections of the QT interval showed QTc prolongation at clinical concentrations. Clinical evaluation of this compound with intense Phase 1 ECG monitoring showed QTc exceeding 10 ms prolongation at the anticipated clinical concentration. Although blood pressure monitoring was not available clinically, two patients did complain of orthostasis when standing. The compound was eliminated from development because of anticipated labeling issues.

GABAergic compound intended for sedation and sleep with no HERG liability was nominated from Discovery. Since GABAergics produce agitation in conscious dogs, it was anticipated that heart rate increases would be observed. Beat-to-beat analyses in sling-trained conscious dogs confirmed that heart rates were increased yet no increases in QT interval beyond the baseline upper 95% confidence bounds for beats with similar RR intervals were observed. These same beats corrected showed extreme QTc prolongation compared to baseline. The compound in traditional Toxicology studies showed QTc prolongation in conscious dogs as well. In human studies, Cmax occurred at 1 hour after dosing and subjects showed a significant decrease in diastolic pressure (6 mmHg compared to time-matched placebo) as they were falling asleep at this time period (the intended activity). This produced a decrease in QT interval (4 ms) and increase in heart rate (8 BPM) that mirrored the response to diastolic blood pressure changes. Analyses of the QT intervals at this time showed increases of 20 and 12 ms in QTc by Bazett and Fridericia corrections. A plot of the QT –RR during sleep indicated a flattening of the relationship similar to normal sleep relationship from Holter studies. However, the data were compared to time-matched placebo, as per E14 guidelines when control subjects were not sleeping and the QT-RR interval relationship is steeper. The compound was terminated from development because of anticipated labeling issues.

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