1. Introduction In recent years, withdrawal of marketed drugs including sertindole, grepafloxacin, and terfenadine owing to prolongation of the length of time between the start of the Q wave and end of the T wave on an electrocardiogram (QT interval) has prompted considerable effort in trying to establish the molecular basis of this potentially lethal… (More)
Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors… (More)
The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.
Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery… (More)