Kathy Derakhchan, PhD, DSP

The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the… Show more

The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aβ reduction in a rat pharmacodynamic model (78% Aβ reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo. Show less

BACKGROUND AND PURPOSE: During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes… Show more

BACKGROUND AND PURPOSE: During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non-human primates (NHPs), previously implanted with a PCT transmitter.
EXPERIMENTAL APPROACH:
Twelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg⁻¹) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics.
KEY RESULTS:
Sotalol attained Cmax values 1-3 hours after dosing, and exhibited dose-proportional exposure. In jacketed NHPs, sotalol dose-dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg⁻¹ sotalol, respectively, compared with time-matched vehicle-treated animals. Overall, JET-derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT.
CONCLUSIONS AND IMPLICATIONS:
The current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint-based ECG because high-density ECG sampling can be collected in unstressed conscious monkeys, over several weeks. Show less

The occurrence of drug-induced arrhythmia in safety pharmacology or toxicology studies is a primary safety concern, but the risk assessment requires an accurate knowledge of background arrhythmia frequency in the test species. The purpose of this study was to determine the normal frequency of arrhythmias in a colony of telemetered cynomolgus monkeys, since there is a data gap in background arrhythmias in this species. To conduct this analysis, continuous ECG data (24 hr) were recorded from 18… Show more

The occurrence of drug-induced arrhythmia in safety pharmacology or toxicology studies is a primary safety concern, but the risk assessment requires an accurate knowledge of background arrhythmia frequency in the test species. The purpose of this study was to determine the normal frequency of arrhythmias in a colony of telemetered cynomolgus monkeys, since there is a data gap in background arrhythmias in this species. To conduct this analysis, continuous ECG data (24 hr) were recorded from 18 telemetry-instrumented monkeys on 3 separate days, over an 8 day period. For each animal, an arrhythmia waveform library was manually created, then applied to the waveform file using EMKA ecgAuto, a pattern recognition-based software application. On day 1, 8/18 monkeys showed at least 1 premature ventricular contraction (PVC; range: 1-12), with 2/18 showing 1 incidence of supraventricular premature complexes (SPC). On day 4, a similar pattern emerged: 5/18
monkeys showed at least 1 PVC (range: 1-12) and 3/18 had 1 incidence of SPC. On day 8, 7/18 NHP displayed at least 1 PVC and 1/18 had a SPC. Other arrhythmias were noted sporadically: right bundle branch block, wandering pacemaker, SA node pause. The pattern of arrhythmia was relatively consistent in each NHP. These findings suggest that a single 24 hr assessment period may be insufficient to determine arrhythmia background. A best practice recommendation is to determine the background arrhythmia rate in each telemetry animal to aid interpretation of potential proarrhythmic properties of new test articles.
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Atrial fibrillation (AF) is the most common cardiac arrhythmia requiring medical therapy, and present treatment modalities are inadequate. Over the past few years, we have learned a great deal about the phenomenon of electrical remodeling, by which rapid atrial activation leads to changes in atrial electrical properties that promote AF initiation and maintenance. This knowledge opens up the possibility that electrical remodeling may itself be a novel therapeutic target in AF. The present paper… Show more

Atrial fibrillation (AF) is the most common cardiac arrhythmia requiring medical therapy, and present treatment modalities are inadequate. Over the past few years, we have learned a great deal about the phenomenon of electrical remodeling, by which rapid atrial activation leads to changes in atrial electrical properties that promote AF initiation and maintenance. This knowledge opens up the possibility that electrical remodeling may itself be a novel therapeutic target in AF. The present paper reviews what is known about the basic mechanisms of atrial electrical remodeling and then discusses the experimental and clinical evidence that remodeling can be prevented by drug therapy. Despite great potential value, the development of pharmacological interventions to prevent atrial electrical remodeling is still in its infancy. Show less