| Abstract
| - Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonistsin an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series ashaving excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasmaand brain. Optimization of this series led to considerable improvements in affinity, functional potency, andpharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that wasorally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat,and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascularmodel compared to other series reported by our group. However, this analogue also led to prolongation ofthe QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functionalblockade of this ion channel.
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