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Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs.
Bioorg Med Chem. 2010 Mar 01; 18(5):1834-43.BM

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.

Authors+Show Affiliations

Dipartimento di Scienze Chimiche, Università di Camerino, via Sant'Agostino 1, 62032 Camerino, Italy. gianfabio.giorgioni@unicam.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20153654

Citation

Giorgioni, Gianfabio, et al. "Design, Synthesis, and Preliminary Pharmacological Evaluation of New Imidazolinones as L-DOPA Prodrugs." Bioorganic & Medicinal Chemistry, vol. 18, no. 5, 2010, pp. 1834-43.
Giorgioni G, Claudi F, Ruggieri S, et al. Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs. Bioorg Med Chem. 2010;18(5):1834-43.
Giorgioni, G., Claudi, F., Ruggieri, S., Ricciutelli, M., Palmieri, G. F., Di Stefano, A., Sozio, P., Cerasa, L. S., Chiavaroli, A., Ferrante, C., Orlando, G., & Glennon, R. A. (2010). Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs. Bioorganic & Medicinal Chemistry, 18(5), 1834-43. https://doi.org/10.1016/j.bmc.2010.01.041
Giorgioni G, et al. Design, Synthesis, and Preliminary Pharmacological Evaluation of New Imidazolinones as L-DOPA Prodrugs. Bioorg Med Chem. 2010 Mar 1;18(5):1834-43. PubMed PMID: 20153654.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs. AU - Giorgioni,Gianfabio, AU - Claudi,Francesco, AU - Ruggieri,Sabrina, AU - Ricciutelli,Massimo, AU - Palmieri,Giovanni F, AU - Di Stefano,Antonio, AU - Sozio,Piera, AU - Cerasa,Laura S, AU - Chiavaroli,Annalisa, AU - Ferrante,Claudio, AU - Orlando,Giustino, AU - Glennon,Richard A, Y1 - 2010/01/25/ PY - 2009/10/02/received PY - 2009/10/13/revised PY - 2010/01/19/accepted PY - 2010/2/16/entrez PY - 2010/2/16/pubmed PY - 2010/6/16/medline SP - 1834 EP - 43 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 18 IS - 5 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/20153654/Design_synthesis_and_preliminary_pharmacological_evaluation_of_new_imidazolinones_as_L_DOPA_prodrugs_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(10)00062-3 DB - PRIME DP - Unbound Medicine ER -