Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs.

Abstract l -DOPA, the immediate biological precursor of dopamine, is still considered the drug of choice in the treatment of Parkinson’s disease. However, therapy with l -DOPA is associated with a number of acute problems. With the aim to increase the bioavailability after oral administration, we designed a multi-protected l -DOPA prodrugs able to release the drug by both spontaneous chemical or enzyme catalyzed hydrolysis. The new compounds have been synthesized and preliminarily evaluated for their water solubility, log  P , chemical stability, and enzymatic stability. The results indicate that the incorporation of the amino acidic moiety of l -DOPA into an imidazoline-4-one ring provides prodrugs sufficiently stable to potentially cross unchanged the acidic environment of the stomach, and to be absorbed from the intestine. They also might be able to release l -DOPA in human plasma after enzymatic hydrolysis. The ability of prodrugs 6a – b to increase basal levels of striatal DA, and influence brain neurochemistry associated with dopaminergic activity following oral administration, as well as the radical-scavenging activity against DPPH for compounds 6a – b and 15a are also reported.