title: Aminocarbonyloxymethyl ester prodrugs of flufenamic acid and diclofenac: suppressing the rearrangement pathway in aqueous media.
abstract: Aminocarbonyloxymethyl ester prodrugs are known to undergo rearrangement in aqueous solutions to form the corresponding N-acylamine side product via an O-->N intramolecular acyl transfer from the carbamate conjugate base. Novel aminocarbonyloxymethyl esters of diclofenac and flufenamic acid containing amino acid amide carriers were synthesized and evaluated as potential prodrugs displaying less ability to undergo rearrangement. These compounds were prepared in reasonable yield by a four-step synthetic method that uses the appropriate N-Boc-protected amino acid N-hydroxysuccinimide ester and secondary amine and chloromethyl chloroformate as key reactants. Their reactivity in pH 7.4 buffer and 80% human plasma at 37 degrees C was assessed by RP-HPLC. The aminocarbonyloxymethyl esters containing a secondary carbamate group derived from amino acids such as glycine or phenylalanine were hydrolyzed quantitatively to the parent drug both in non-enzymatic and enzymatic conditions, with no rearrangement product being detected. The oral bioavailability in rats was determined for selected diclofenac derivatives. These derivatives displayed a bioavailability of 25 to 68% relative to that of diclofenac, probably due to their poor aqueous solubility and lipophilicity. These results suggest that further optimization of aminocarbonyloxymethyl esters as potential prodrugs for non-steroidal anti-inflammatory drugs require the use of amino acid carriers with ionizable groups to improve aqueous solubility.
authors.affiliation: 1 CECF, Faculdade de Farmácia da Universidade de Lisboa, Lisboa Codex, Portugal.
authors.forename: Lina
authors.initials: L
authors.lastname: Ribeiro
authors.forename: Nuno
authors.initials: N
authors.lastname: Silva
authors.forename: Jim
authors.initials: J
authors.lastname: Iley
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
authors.forename: Tomi
authors.initials: T
authors.lastname: Järvinen
authors.forename: Hélder
authors.initials: H
authors.lastname: Mota-Filipe
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Eduarda
authors.initials: E
authors.lastname: Mendes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001682:Biological Availability; D002021:Buffers; D002264:Carboxylic Acids / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004008:Diclofenac / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D004355:Drug Stability; D004952:Esters / Q000737:chemistry; D005439:Flufenamic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis*; D051381:Rats; D017208:Rats, Wistar; D014867:Water / Q000737:chemistry*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002021:Buffers; D002264:Carboxylic Acids; D004952:Esters; D011355:Prodrugs; D014867:Water; D004008:Diclofenac; D005439:Flufenamic Acid