Using Kobayashi's modification of the Grieco reaction, we were able to synthesize diverse 4-phenylthio-1,2,3,4-tetrahydroquinolines. These intermediates were oxidized and subsequently pyrolized to provide the corresponding quinolines. This new approach to 2-substituted quinolines was exemplified by liquid-phase production of a 25-member library. This was extended to solid-phase chemistry, starting from (l)-4-nitrophenylalanine on Wang resin, for production of a 16-member library. The latter compounds possess potentially interesting VLA-4 antagonist properties.

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A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC 50 s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.

The conformations of three endothelin antagonists, a cyclic pentapeptide, a linear tripeptide and a linear hexapeptide, are compared by 'H NMR and molecular dynamics. The three analogues have a Leu and a ~Trp side chain which are oriented parallel, and an acidic group next to the ~Trp residue.

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