Page 152 - Medicinal Chemistry Self Assessment

2.9 Aripiprazole 141

6. Shown below are three known metabolites of aripiprazole. Identify the metabolic transformations
7. Shown below are or a phase II transformation.
that would be required to form each of the metabolites. For each metabolic transformation, indicate
if it is a phase I transformation or a phase II transformation.

Metabolite A

Metabolite B

Metabolite C

Answer
Answer
Metabolite A: Aromatic oxidation, phase I
Metabolite A: Aromatic oxidation, phase I
Note: This is somewhat of an unexpected metabolite because the presence of halogen substitutents
Metabolite B: Benzylic oxidation, phase I
on the aromatic ring generally deactivates these rings from oxidation. The difference in this partic-
Note: Due to the ability to form a conjugated system, this secondary hydroxyl group readily
ular drug molecule is the presence of an adjacent aromatic amine. This aromatic amine can donate
undergoes dehydration to form the following metabolite.
electrons into the ring via resonance and either override or neutralize the electronic effects of the
chloro groups, thus allowing for aromatic oxidation.

Metabolite B: Benzylic oxidation, phase I
Dehydration allows
Note: Due to the ability to form a conjugated system, this secondary hydroxyl group readily under-
goes dehydration to form the following metabolite. conjugation between
the amide and the
aromatic ring.