The SCH 48461 contains a lactam ring which is prone to hydrolysis by cytochrome P 450 enzymes. Also, the methyl groups are likely to undergo oxidation, thus making it polar. A polar metabolite is easily excreted from the body. Methyl groups may also be conjugated in phase II biotransformation reactions which would result in the rapid excretion of the molecule.
There are a number of modifications which can be made to reduce metabolic susceptibility of SCH 48461:
1) One modification would be the introduction of a fluoro substituent at the para position to prevent oxidation of aromatic rings.
2) Another modification could be the replacement or entire removal of the methoxy groups at the aromatic rings.
3) Lastly, stearic shielding could be implemented by introducing substitutes on the aromatic ring attached to the nitrogen of the lactam ring. This will prevent the ring from opening by hydrolysis.
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