Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase.

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 IC50s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.

Lead optimization of thiazolo[5,4-c]piperidines: 3-cyclobutoxy linker as a key spacer for H(3)R inverse agonists.

The simpler, the better: H(3) histamine receptor (H(3)R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H(3)R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.

Imidazopyridines as VLA-4 integrin antagonists.

We describe a novel series of imidazopyridine substituted phenylalanines which are potent VLA-4 antagonists. A wide variety of substituents are tolerated as replacements for the pendant 3-pyridyl ring. A clear structure-activity relationship was identified around the substitution of the 3-amino-cyclobut-2-enone portion of the molecule.

2,6-Quinolinyl derivatives as potent VLA-4 antagonists.

A new series of 2,6-quinolinyl derivatives was prepared leading to potent low nanomolar VLA-4/VCAM-1 antagonists.

New synthetic pathway to diverse 2-substituted quinolines based on a multicomponent reaction: solution-phase and solid-phase applications.

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.