Document Detail

Aminocarbonyloxymethyl ester prodrugs of flufenamic acid and diclofenac: suppressing the rearrangement pathway in aqueous media.
MedLine Citation:
PMID:  17206608     Owner:  NLM     Status:  MEDLINE    
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.
Lina Ribeiro; Nuno Silva; Jim Iley; Jarkko Rautio; Tomi Järvinen; Hélder Mota-Filipe; Rui Moreira; Eduarda Mendes
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Archiv der Pharmazie     Volume:  340     ISSN:  0365-6233     ISO Abbreviation:  Arch. Pharm. (Weinheim)     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-04-11     Completed Date:  2007-05-04     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0330167     Medline TA:  Arch Pharm (Weinheim)     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  32-40     Citation Subset:  IM    
1 CECF, Faculdade de Farmácia da Universidade de Lisboa, Lisboa Codex, Portugal.
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MeSH Terms
Administration, Oral
Anti-Inflammatory Agents, Non-Steroidal / administration & dosage,  blood,  chemical synthesis*,  pharmacokinetics
Biological Availability
Carboxylic Acids / chemistry
Chromatography, High Pressure Liquid / methods
Diclofenac / administration & dosage,  analogs & derivatives,  blood,  chemical synthesis*,  pharmacokinetics
Drug Stability
Esters / chemistry
Flufenamic Acid / analogs & derivatives,  chemical synthesis*
Hydrogen-Ion Concentration
Molecular Structure
Prodrugs / chemical synthesis*
Rats, Wistar
Water / chemistry*
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Buffers; 0/Carboxylic Acids; 0/Esters; 0/Prodrugs; 15307-86-5/Diclofenac; 530-78-9/Flufenamic Acid; 7732-18-5/Water

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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