into a heat map and binned into 8 functional categories (stereotypy,excitation, sedation, pain, autonomic, reflex, other, and death);statistical analyses of the Irwin score were subsequently performed.We describe the methodology in more detail and present results forrepresentative positive and negative controls (amphetamine, diazepam,chlorpromazine, atropine, propranolol) and three novel compoundstargeted for clinical development. Results demonstrate that quantifica-tion of Irwin Scores, and the graphical representation of results binnedinto functional categories, enables a clear visualization of dose-responseand compound-related effects on CNS function.

doi:10.1016/j.vascn.2010.11.134

Poster Number: 131Board Number: 70

Eliminating cardiac ion channel liabilities in a histamine receptorantagonist programvia ion channelmodeling and electrophysiologyClemens Moeller

Evotec AG, Hamburg, Germany

The histamine system constitutes one of the most importantbrain-activating systems and regulates several brain functions. Whilehistamine receptor antagonists have potential in a number oftherapeutic areas, these antagonists often suffer from cardiac sideeffects, particularly due to hERG liability. In several cases this liabilityhas stopped compounds or series from being progressed into pre-clinical and clinical development. In the planning and executionof a Histamine receptor 3 (H3) antagonist project, the potentialhERG liability was therefore already addressed at early stages of theprogramme. Electrophysiological hERGmeasurements of a sub-set ofcompounds from the medicinal chemistry iteration cycles wereperformed. The results were used to establish a structure-activityrelation (SAR) with respect to hERG. Using structural information ofthe channel, a 2D and 3D in silico model were established to predicthERG liability. Potential liabilities on further cardiac ion channelswere assessed by early measurements in a Zebrafish cardiac model.Data presented will include iteration cycles employing differentelectrophysiological platforms, and correlation between ion channelmodels, electrophysiology and Zebrafish observations. The resultsfor the H3 antagonist lead series will be summarized. The 3Dcomputational model supported themedicinal chemistry to generatea series with high affinity to the H3 target with avoiding liabilityon hERG.

doi:10.1016/j.vascn.2010.11.135

Poster Number: 132Board Number: 71

Magnesium prevents drug-induced torsades de pointes in therabbit model of ventricular hypertrophy: Arrhythmia repeatabilityand instabilityAnusk Kijtawornrata, Yaowalak Panyasingb, Carlos del Rioa,Jay J. Schmidta, Lindsey Sneddena, Robert L. Hamlina,b

aQTest Labs, LLC, Columbus, OH, United StatesbThe Ohio State University, Columbus, OH, United States

Concern over drug-induced Torsades de Pointes (TdP) is im-portant in drug development. Animal model of right ventricular

hypertrophy (RVH) in rabbits allows detection of not onlyprolongation of QT/QTc and QT instability, but also of TdP. However,the presence and importance of QT/QTc duration and QT instability,and the repeatability of production of TP by known torsadogens hasnot been addressed. This study was designed to determine therepeatability of production of, and to assess the role of prolongatonof QT/QTc and beat-to-beat variability in predicting TdP. Incidenceof TdP was measured in 7 rabbits with RVH given 10 minuteinfusions of 5, 10, and 20 ug/kg of dofetilide. Rabbits were giveneither nothing or a bolus of 60 mg/kg of magnesium sulfate(MgSO4) followed by a continuous infusion (1.0 mg/kg/min). A leadII ECG was recorded. Rabbits receiving MgSO4 had a reducedincidence (0/7) of early after depolarizations and no incidence ofTdP when compared to rabbits receiving no MgSO4 (7/7) (p<0.05).Lengthening of both QT and QTc was less in rabbits receiving MgSO4,but there was no difference in QT instability. Thus QT instability(present, equally, in rabbits both with or without MgS04) may notnecessarily be predictive of TdP, whereas the degree or prolongationof QT and QTc appears more relevant in this model. Furthermore,because rabbits were exposed to the torsadogen on numerousoccasions and developed TdP, production of TdP in rabbits with RVHis reproducible.

doi:10.1016/j.vascn.2010.11.136

Poster Number: 133Board Number: 72

Comparison of standard agents in the alpha-chloralose andurethane anaesthetised dog and other dog modelsChantelle E. Connaughton, Neil S. Brunton

Pfizer Ltd., Sandwich, United Kingdom

Assessment of cardiovascular safety using the anaesthetised dogat Pfizer has been performed mainly in dogs anaesthetised withisoflurane. However, isoflurane increases sympathetic drive bydecreasing vagal activity and leads to a high heart rate/lowcontractility model with basal haemodynamic levels that are unlikethat of a conscious dog. Animals under alpha-chloralose and urethane(C&U) anaesthesia are reported to have cardiovascular responsesvirtually indistinguishable from that of a resting conscious animal.In order to validate the C&U model the cardiovascular effects ofpropafenone (Class 1 antiarrhythmic/sodium channel blocker),doxazosin (alpha1 adrenoceptor antagonist), verapamil (calciumchannel blocker) and milrinone (PDE3i) were examined in C&Uanaesthetised dogs and the results were compared to those producedin previous conscious and isoflurane anaesthetised dog studies. C&Uanaesthetised dogs basal haemodynamic parameters were similar toconscious dog basal parameters. There was good concordance forheart rate between C&U anaesthetised dogs and conscious dogs forverapamil, milrinone and doxazosin. By contrast doxazosin andverapamil in the isoflurane anaesthetised dog showed a differenthaemodynamic profile to the C&U dogs. C&U dogs treated withpropafenone showed decreases in heart rate but there were increasesobserved in conscious dogs however, both groups did show anincrease in QRS. Overall cardiovascular data from the C&U anaes-thetised dogs were more similar to those obtained from consciousrather than isoflurane anaesthetised dogs.

doi:10.1016/j.vascn.2010.11.137

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