Phenyl carbamates of amino acids as prodrug forms for protecting phenols against first-pass metabolism

Hansen, J. G.; Mørk, Niels; Bundgaard, Hans

doi:10.1016/0378-5173(92)90017-v

Cited by 22 publications

(17 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This notion is reinforced by the variability of the rates from one compound to the other. Hansen 38 and co-workers have demonstrated that the predominant rate-accelerating component of plasma (human in that study) is albumin.…”

Section: Resultsmentioning

confidence: 58%

“…The carbamoyl moiety provides a versatile protecting group for phenols (-OH → -OC( = O)NR′R″) 37 38 , which allows fine-tuning of the properties of the molecule since the two substituents on nitrogen, R′ and R″, can be tailored to modulate the stability and physicochemical properties of the resulting prodrug. Several prodrugs have been developed to improve oral bioavailability of phenolic compounds 39 40 41 but surprisingly there are only few examples of carbamate ester prodrugs of polyphenols.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Amino Acid Carbamates As Prodrugs Of Resveratrol

Mattarei

Azzolini

Spina

et al. 2015

Sci Rep

View full text Add to dashboard Cite

Resveratrol (3, 5, 4′-trihydroxy-trans-stilbene), a plant polyphenol, has important drug-like properties, but its pharmacological exploitation in vivo is hindered by its rapid transformation via phase II conjugative metabolism. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, stability and in vivo pharmacokinetic behaviour of prodrugs of resveratrol in which the OH groups are engaged in an N-monosubstituted carbamate ester (-OC(O)NHR) linkage with a natural amino acid (Leu, Ile, Phe, Thr) to prevent conjugation and modulate the physicochemical properties of the molecule. We also report a convenient, high-yield protocol to obtain derivatives of this type. The new carbamate ester derivatives are stable at pH 1, while they undergo slow hydrolysis at physiological pH and hydrolyse with kinetics suitable for use in prodrugs in whole blood. After administration to rats by oral gavage the isoleucine-containing prodrug was significantly absorbed, and was present in the bloodstream as non-metabolized unaltered or partially deprotected species, demonstrating effective shielding from first-pass metabolism. We conclude that prodrugs based on the N-monosubstituted carbamate ester bond have the appropriate stability profile for the systemic delivery of phenolic compounds.

show abstract

Section: Resultsmentioning

confidence: 58%

mentioning

confidence: 99%

Amino Acid Carbamates As Prodrugs Of Resveratrol

Mattarei

Azzolini

Spina

et al. 2015

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Thus, phenol was selected as a model drug substance because the metabolism has been studied extensively [28][29][30][31]. Further, it has been used previously as a model compound in prodrug related studies aiming at the circumvention of first-pass metabolism [32][33][34][35]. A series of carbonate ester bioreversible derivatives of phenol (Table 1) was synthesized, including derivatives possessing a fatty acid-like structure as a means for building in affinity for HSA in the structures.…”

Section: Introductionmentioning

confidence: 99%

Bioreversible Derivatives of Phenol. 2. Reactivity of Carbonate Esters with Fatty Acid-like Structures Towards Hydrolysis in Aqueous Solutions

Østergaard

Larsen

2007

Molecules

View full text Add to dashboard Cite

A series of model phenol carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 -12.5) at 37 o C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, depending on the selected pro-moieties (alkyl and aryl substituents). The observed reactivity differences could be rationalized by the inductive and steric properties of the substituent groups when taking into account that the mechanism of hydrolysis may change when the type of pro-moiety is altered, e.g. n-alkyl vs. t-butyl. Hydrolysis of the phenolic carbonate ester 2-(phenoxycarbonyloxy)-acetic acid was increased due to intramolecular catalysis, as compared to the derivatives synthesized from ω-hydroxy carboxylic acids with longer alkyl chains. The carbonate esters appear to be less reactive towards specific acid and base catalyzed hydrolysis than phenyl acetate. The results underline that it is unrealistic to expect that phenolic carbonate ester prodrugs can be utilized in ready to use aqueous formulations. The stability of the carbonate ester derivatives with fatty acid-like structures, expected to interact with the plasma protein human serum albumin, proved sufficient for further in vitro and in vivo evaluation of the potential of utilizing HSA binding in combination with the prodrug approach for optimization of drug pharmacokinetics. Molecules 2007, 12 2397

show abstract

“…Phenol is subject to hepatic metabolism [29][30][31][32], the main metabolites being phenyl glucuronide and phenyl sulphate. Furthermore, it has previously been used as a model compound in prodrug related studies aiming at the circumvention of first-pass metabolism [36][37][38][39]. …”

Section: Resultsmentioning

confidence: 99%

“…Best characterized is probably the catalysis of p-nitrophenyl acetate decomposition [26,63,64] which will discussed further below. Compounds studied in a prodrug context include nicotinic acid esters [65,66], acetylsalicylic acid [61], and carbamates of phenol [36,38]. Furthermore, hydrolysis of long chain aryl esters has been found to be catalyzed by HSA [62].…”

Section: Hydrolysis In Hsa Solutionmentioning

confidence: 99%

Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media

Østergaard

Larsen

2007

Molecules

View full text Add to dashboard Cite

Abstract:With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving the pharmacokinetics of drug substances, a series of model carbonate ester prodrugs of phenol, encompassing derivatives with fatty acid-like structures, were characterized in vitro. Stability of the derivatives was studied in aqueous solution, human serum albumin solution, human plasma, and rat liver homogenate at 37 o C. Stability of the derivatives in aqueous solution varied widely, with half-lives ranging from 31 to 1.7 × 10 4 min at pH 7.4and 37 o C. The carbonate esters were subject to catalysis by plasma esterases except for the t-butyl and acetic acid derivatives, which were stabilized in both human plasma and human serum albumin solutions relative to buffer. In most cases, however, hydrolysis was accelerated in the presence of human serum albumin indicating that the derivatives interacted with the protein, a finding which was confirmed using the p-nitrophenyl acetate kinetic assay. Different human serum albumin binding properties of the phenol model prodrugs with fatty acid-like structure and neutral carbonate esters were observed. In the context of utilizing plasma protein binding in combination with the prodrug approach for optimizing drug pharmacokinetics, the esterase-like properties of human serum albumin towards the carbonate esters potentially allowing the protein to act as a catalyst of parent compound regenerations is interesting.

show abstract

Phenyl carbamates of amino acids as prodrug forms for protecting phenols against first-pass metabolism

Cited by 22 publications

References 26 publications

Amino Acid Carbamates As Prodrugs Of Resveratrol

Amino Acid Carbamates As Prodrugs Of Resveratrol

Bioreversible Derivatives of Phenol. 2. Reactivity of Carbonate Esters with Fatty Acid-like Structures Towards Hydrolysis in Aqueous Solutions

Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media

Contact Info

Product

Resources

About