A new potential prodrug to improve the duration of L-dopa: L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine.
L-3-(3-Hydroxy-4-pivaloyloxyphenyl)alanine (1, NB-355) is a novel L-dopa prodrug. After oral administration with carbidopa in rats, 1 demonstrated 2.3 times longer duration (MRT) and 1.4 times larger bioavailability (AUC) on plasma L-dopa concentrations than those of L-dopa itself. Similar results were obtained in dogs. The prolonged profile of L-dopa was parallel to that of carbidopa, and the intact ester was undetectable in rat plasma. After intravenous administration in rats, 1 was converted quickly and completely to L-dopa in the systemic circulation. It was also noted that the oral LD50 value of 1 was greater than 6 g/kg in mice. These data suggest that 1 will offer long-lasting L-dopa therapy for the treatment of Parkinson's disease with little concern about toxicity.
Ihara
M
M
Central Research Laboratories, Banyu Pharmaceutical Company, Ltd., Tokyo, Japan.
Tsuchiya
Y
Y
Sawasaki
Y
Y
Hisaka
A
A
Takehana
H
H
Tomimoto
K
K
Yano
M
M
D000818:Animals; D001682:Biological Availability; D002230:Carbidopa / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D007980:Levodopa / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
D011355:Prodrugs; C061031:L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine; D014443:Tyrosine; D007980:Levodopa; D002230:Carbidopa; C008404:3-methoxytyrosine