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Rautio, Jarkko; Nevalainen, Tapio; Taipale, Hannu; Vepsäläinen, Jouko; Gynther, Jukka; Pedersen, Tina Bugge; Järvinen, Tomi

doi:10.1023/a:1018981010047

Cited by 34 publications

(9 citation statements)

References 9 publications

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“…1) [17]. The presence of the basic a-amino group has been reported to improve the water-solubility of prodrugs 1, but unfortunately, usually leads to chemically unstable compounds [17,18]. This is due to the strong electron-withdrawing effect of the protonated amino group at physiological pH and to the ability of the unprotonated amino group to enhance hydrolysis via nucleophilic or general-base catalysis [16] and to undergo intramolecular rearrangement to form an amide [17].…”

Section: Introductionmentioning

confidence: 99%

Aminocarbonyloxymethyl Ester Prodrugs of Flufenamic Acid and Diclofenac: Suppressing the Rearrangement Pathway in Aqueous Media

Ribeiro

Silva

Iley

et al. 2007

Archiv der Pharmazie

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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.

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Section: Introductionmentioning

confidence: 99%

Aminocarbonyloxymethyl Ester Prodrugs of Flufenamic Acid and Diclofenac: Suppressing the Rearrangement Pathway in Aqueous Media

Ribeiro

Silva

Iley

et al. 2007

Archiv der Pharmazie

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“…For a rationally designed prodrug intended to prolong the half-life of the active moiety, the metabolic lability should be sufficient and continuous. Preliminary metabolic stability was assessed in human plasma and human liver microsomes The profile of disappearance of each prodrug followed a pseudo-first-order trend, and half-lives were calculated from the linear slopes of logarithmic plots of remaining prodrug over time [30]. Results are listed and compared in Table 3.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Liguzinediol Mono- and Dual Ester Prodrugs as Promising Inotropic Agents

Zhang

Wen

et al. 2014

Molecules

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Abstract:The potent positive inotropic effect, together with the relatively low safety risk of liguzinediol (LZDO), relative to currently available inotropic drugs, has prompted us to intensively research and develop LZDO as a potent positive inotropic agent. In this study, to obtain LZDO alternatives for oral chronic administration, a series of long-chain fatty carboxylic mono-and dual-esters of LZDO were synthesized, and preliminarily evaluated for physicochemical properties and bioconversion. Enhanced lipophilic properties and decreased solubility of the prodrugs were observed as the side chain length increased. All esters showed conspicuous chemical stability in phosphate buffer (pH 7.4). Moreover, the enzymatic hydrolysis of esters in human plasma and human liver microsomes confirmed that the majority of esters were converted to LZDO, with release profiles that varied due to the size and structure of the side chain. In vivo pharmacokinetic studies following oral administration of monopivaloyl (M5), monodecyl (M10) and monododecyl (M12) esters demonstrated the evidently extended half-lives relative to LZDO dosed alone. In particular the monopivaloyl ester M5 exhibited an optimal pharmacokinetic profile with appropriate physiochemical characteristics.

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“…In recent years, polymeric drug derivatives, in which the drug molecules are linked to polymeric matrices through covalent bonding of limited stability in the physiological environment, are receiving considerable attention (8)(9)(10)(11)(12)(13)(14). This is believed to be one of the most promising ways to modify the pharmacokinetics of the drugs and to achieve preferential localization to target sites.…”

Section: Synthesis and Evaluation Of A Nonsteroidalmentioning

confidence: 99%

Synthesis and Evaluation of a Nonsteroidal Anti-inflammatory Polymeric Prodrug for Sustained and Site-Specific Delivery

Chandrasekar

Ravichandran

Nanjan

et al. 2001

Drug Development and Industrial Pharmacy

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A new polymerizable drug derivative of diclofenac sodium was synthesized and characterized in terms of melting point, elemental analysis, and infrared spectroscopy. It was then polymerized to obtain a new polymeric prodrug. The prodrug was evaluated for its viscosity, drug content, and in vitro drug release behavior at pH 1.2 and 7.2. The in vitro studies showed that the drug release takes place predominantly at the higher pH and in a sustained manner, as hypothesized. Stability at room temperature, bioavailability, and ulcer-inducing effect of the polymeric prodrug were also studied. The investigations showed complete drug absorption from the polymeric prodrug with a statistically significant decrease in ulcer scoring effect, thus showing its potentialfor site-specific and sustained drug delivery.

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Abstract: Combinations of adequate aqueous solubility and lipophilicity of naproxen aminoacyloxyalkyl prodrugs having fast rates of enzymatic hydrolysis resulted in improved dermal delivery of naproxen.

Cited by 34 publications

References 9 publications

Aminocarbonyloxymethyl Ester Prodrugs of Flufenamic Acid and Diclofenac: Suppressing the Rearrangement Pathway in Aqueous Media

Aminocarbonyloxymethyl Ester Prodrugs of Flufenamic Acid and Diclofenac: Suppressing the Rearrangement Pathway in Aqueous Media

Synthesis and Biological Evaluation of Liguzinediol Mono- and Dual Ester Prodrugs as Promising Inotropic Agents

Synthesis and Evaluation of a Nonsteroidal Anti-inflammatory Polymeric Prodrug for Sustained and Site-Specific Delivery

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