a Abbreviations: hERG, human ether-a-go-go gene related product; TdP, torsades de pointes; minK, minimal potassium channel; KvLQT1, potassium voltage-gated channel subfamily KQT member 1; Kir2, inward rectifier potassium channel 2; IKr, potassium voltage-gated channel ether-a-go-go protein; IKs, slow voltage producing potassium channel β subunit; KcsA, Streptomyces liVidans potassium channel; MthK, Methanobacterium thermoautotrophicum potassium channel; KvAP, Aeropyrum pernix voltagedependent potassium channel; APD, action potential duration; MAP, monophasic action potential; GRIND, grid independent descriptors; MLR, multiple linear regression; DSM, discrete structural modifications; ZI, zwitterion.

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Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.

Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.

A novel CB1 receptor agonist lead series was identified using a high-throughput screening approach. The initial screen afforded a single confirmed hit with poor water solubility. Structural variations were explored with the aim of introducing water solubility and improving potency. This led to the discovery of Org 28611, a potent, water soluble CB1 receptor agonist, which was selected for clinical evaluation as a potential intravenous analgesic agent.

Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.

2,6-disubstituted N-aryl ureas rotate slowly about their Ar-N bonds and can exist as separable atropisomers. They also react remarkably diastereoselectively, with the urea axis controlling new stereogenic centers with high fidelity in a variety of nucleophilic and electrophilic addition reactions. The sense of diastereoselectivity in lateral lithiation-electrophilic quench reactions is electrophile-dependent and appears to be the result of stereospecific reaction with one of two interconvertible diastereoisomeric organolithiums.