title: Hydrolysis and acyl migration of a catechol monoester of L-dopa: L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine.
abstract: Hydrolysis and acyl migration studies on L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (1, NB-355), which produced long-lasting plasma L-dopa levels after oral dosing, have been conducted. Compound 1 exists as pure 4-O-pivaloyl-L-dopa in the solid state, but it converts rapidly to a mixture of the 3- and 4-O-isomers in solution. The rate of acyl migration increased with increases in pH and temperature, and the content of the 4-O-isomer in the equilibrium state was 53-59%. The hydrolysis rate of 1 to L-dopa (6) also increased with increases in pH and temperature, and accelerated steeply at neutral and alkaline pH. The rapid hydrolysis at neutral pH was not observed with O-pivaloyl-L-tyrosine (3), di-O-pivaloyl-L-dopa (4), or L-dopa methyl ester (5). Because of this chemical lability, 1 was hydrolyzed in rat plasma far faster than the other tested catechol esters. However, in rat intestinal homogenate at pH 6.0, 1 was hydrolyzed at the slowest rate among the tested esters, predominantly by a diisofluorophosphate (DFP)-sensitive esterase. Thus, 1 showed a unique in vitro profile on hydrolysis and acyl migration due to the existence of a neighboring hydroxyl group. The stability of 1 in the intestine might be essential for the long-lasting plasma L-dopa profile after oral dosing of 1.
authors.affiliation: Central Research Laboratories, Banyu Pharmaceutical Company, Ltd., Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ihara
authors.forename: S
authors.initials: S
authors.lastname: Nakajima
authors.forename: A
authors.initials: A
authors.lastname: Hisaka
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Y
authors.initials: Y
authors.lastname: Sakuma
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Kitani
authors.forename: M
authors.initials: M
authors.lastname: Yano
mesh_terms: D000215:Acylation; D000818:Animals; D002021:Buffers; D055598:Chemical Phenomena; D002621:Chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D007980:Levodopa / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012996:Solutions; D013696:Temperature
chemical_list: D002021:Buffers; D012996:Solutions; C061031:L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine; D007980:Levodopa