In addition, an amino acid promoiety improves the water solubility of the prodrug 12. Amino acids as promoieties in prodrug design and development. Attachment of amino acids to the parent via a carbonate or carbamate and use of amino acid side chains, which offer a wealth of functional groups e. This study characterized the cellular uptake mechanism and hydrolysis of the amino acid ester prodrugs of nucleoside antiviral drugs in the transiently transfected caco2 cells overexpressing a human intestinal peptide transporter, hpeptl caco2hpeptl cells. Amino acid prodrug strategy has been proved to be an efficient and successful way in the drug design, leading to the development of brivanib alaninate, valacylovir, valganciclovir 11 and rm5061. The lamino acid esters were better prodrugs than the corresponding d or d, lisomers, suggesting the involvement of a stereoselective transporter. Synthesis, hydrolysis studies and phamacodynamic profiles. Most of amino acid prodrugs are either esters or amides, in which amine or carboxylic group of amino acid is attached to hydroxyl, amine or carboxyl group of drug moiety. A series of amino acid prodrugs of nvr3778, a potent antihbv candidate currently under phase ii clinical trial, were designed and synthesized as new antihbv agents. The con cept was proposed some 30 years ago albert. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. In vitro evaluation of amino acid prodrugs of novel antitumour 24.
Moreover, various amino acid transporters are expressed in brushborder membranes of intestinal epithelial cells known to play a significant role in the absorption of several amino acid prodrugs. Valacyclovirase is a valuable target for amino acid ester prodrug based oral drug delivery enhancement strategies. Low water solubility, poor stability and low permeability through biological membranes often hinder the clinical development of biologically active peptides 3. At the top of each column in the matrix is an amino acid that is boxed. The hydrolysis of carboxylic acid ester prodrugs hydrolysis.
In socalled codrugs mutual prodrugs, multiple prodrugs, a prodrug is formed from two pharmacologically active agents coupled together into a single molecule, and act as promoieties of each other. Amino acid ester prodrugs of nucleoside agents have been. Also, prodrugs can be used as precursors in biological conversion pathways, as is the case with ldopa, a prodrug of dopamine. Examples of codrugs include sulfapyridine 5aminosalicylic acid, indomethacin paracetamol, ldopa. Feb 04, 20 in the cyclic phosphonate ester prodrugs, one phosphonic acid oh group of the anps is masked via intramolecular cyclization with the hydroxyl group to afford the cyclic form of the drug figure 2. Design, synthesis, and pharmacokinetic evaluation of. In vitro evaluation of amino acid prodrugs of novel antitumour 24amino3methylphenylbenzothiazoles, submitted for publication. Synthesis and evalution of amide prodrugs of diclofenac surender kumar 1, d.
Engelking, in textbook of veterinary physiological chemistry third edition. The present invention is also directed to pharmaceutical compositions containing same. Chemical stability and bioactivation of amino acid. The essential amino acids are precursors to the neurotransmitters associated with depressions.
The expanding role of prodrugs in contemporary drug design. Pharmacokinetics of dapsone and amino acid prodrugs of. Preclinical evaluation of amino acid prodrugs of novel. Ten prodrugs of fb were synthesized by amidation with ethyl esters of amino acids, namely, glycine, lphenylalanine, ltryptophan, lvaline, lisoleucine. Jun 17, 2003 prodrugs that incorporate an amidomethyl, an aminomethyl, or another fragmentable pro. Penta acetyl prodrug of gitoxin has four to five times more aqueous solubility.
Small neutral amino acid ester prodrugs of acyclovir. To evaluate in vivo corneal absorption of the amino acid prodrugs of acyclovir acv using a topical well model and microdialysis in rabbits. Most of the amino acid pro drugs are either esters or amides, in which an. The carboxylic acid functional group adds to the hydrophilicity of the drug as well as to its polarity and this may impede the bioavailability. By taking advantage of the cytotoxic effect of nitric oxide no and pept1 for moleculetargeted drug delivery, a series of amino acid dipeptide diester prodrugs of nodonating oleanolic acid derivatives were designed and synthesized. George clinical pharmacology group, southamptongeneral hospital, southamptons094xy the term prodrug is usually applied to com poundsthat are inactive in their parent forms but which, after administration, are chemically transformed to the active derivative. Amino acid ester hydrolase journal of biological chemistry. The phenytoin prodrugs were obtained by esterification of bis2. Moiety that contains an amino group prodrugs that incorporate an oxodioxolylmethyl pro. Amino acid ester prodrugs of nucleoside and nucleotide. Acyclic nucleoside analogues, antiherpetics, antiretrovirals, cidofovir, peptidomimetics, prodrugs, tyrosine.
As shown in figure 2, shpmpc 1, and shpmpa 2, incorporate a hydroxymethylene function in their structure, which is able to esterify the anp phosphonic acid group intramolecularly, producing cyclic forms of the anps, chpmpc 3 and chpmpa 4. The new prodrugs were expected to have better lipophilicity, reduced gastric irritancy. Thus, a variety of alkyl ester prodrugs 2, 3, phosphoramidate prodrugs, photoactivated prodrugs, and amino acid ester prodrugs have been examined as potential alternatives to floxuridine. Pdf amino acids in the development of prodrugs researchgate. In the present research work, we synthesize some amide prodrugs of diclofenac by treating the parent drug with amino acid derivatives. The concept of the amino acid phosphonate ester prodrug approach. Diclofenac was made to react with derivatives of amino. The nmonosubstituted carbamate bond is a convenient linker for prodrugs of resveratrol 60 which has been coupled in this study with amino acid promoieties. Amino acid ester prodrugs of nucleoside agents have been shown to be substrates for the pept1 peptide transporter 7. Amino acid prodrugs meet the criteria of aqueous solubility, chemical stability and quantitative reversion to parent molecule, and thus are.
Stability of lalanineacv aacv, lserineacv sacv, lisoleucineacv iacv. Cellular uptake mechanism of amino acid ester prodrugs in. Combination of amino aciddipeptide with nitric oxide. Institute of organic chemistry and biochemistry, academy of sciences of the czech republic, v. New watersoluble antiviral compounds also use ester aminoacid prodrugs to increase solubility with a bicyclic nucleoside subunit. The present invention is directed to a prodrug comprised of an amino acid bonded to a medicament or drug having a hydroxy, amino, carboxy or. Pdf ocular pharmacokinetics of acyclovir amino acid ester. Sixty three per cent of its administered dose was excreted as acyclovir in the urine, a considerable improvement over acyclovir itself, for which. Most of the amino acid prodrugs are either esters or amides, in which an. Except for 1e, all of them displayed roughly comparable antihbv activity ic 50, 0. Moiety prodrugs of active carboxylic acids esterified with a phenol or hydroxylamine. However,5aminiosalicylic acid is the active agent andmostunwanited effects of sulphasalazine relate to systemic absorption of.
The major problem in designing amine prodrugs is the general robustness of amine derivatives. By taking advantage of the cytotoxic effect of nitric oxide no and pept1 for moleculetargeted drug delivery, a series of amino aciddipeptide diester prodrugs of nodonating oleanolic acid derivatives were designed and synthesized. Prodrugs that incorporate an oxodioxolylmethyl pro. Amino acid ester prodrugs of nucleoside and nucleotide antivirals. Amino acid prodrugs meet the criteria of aqueous solubility, chemical stability and quantitative. Eighteen amino acid esters of the antiherpetic drug, acyclovir, were synthesized as potential prodrugs for oral administration. This amino acid prodrug was designed to have less abuse potential than other amphetamines due to the slower release of the active parent. Though l dopa is highly polar, it is actively transported through specific lamino acid active transport mechanism and regenerates dopamine by decarboxylation.
To synthesize amino acid ester prodrugs of floxuridine fudr and to investigate the effects of structure, stereochemistry, and site of esterification of promoiety on the rates of hydrolysis of these prodrugs in caco2 cell homogenates. The impurities were generally the known amino acid ester prodrugs or the parent drug. Essential amino acids an overview sciencedirect topics. To increase aqueous solubility esterification with amino acids is done. In vitro evaluation of amino acid prodrugs of novel antitumour 24 amino 3methylphenylbenzothiazoles, submitted for publication.
Naltrexol the present study was divided between two different drug delivery goals, each involving naltrexone ntx or its active metabolite, 6. Dec 20, 2017 most of amino acid prodrugs are either esters or amides, in which amine or carboxylic group of amino acid is attached to hydroxyl, amine or carboxyl group of drug moiety. Amino acid ester prodrugs of acyclovir sage journals. Aug 31, 2011 most of the amino acid prodrugs are either esters or amides, in which an.
Conjugating specific amino acid with a carboxylic acid containing drug can make them substrates for pept1, thus enhancing the absorption of the parent drug. Oct 14, 2015 the nmonosubstituted carbamate bond is a convenient linker for prodrugs of resveratrol 60 which has been coupled in this study with amino acid promoieties. The lform of amino acids occurs naturally and prodrugs utilizing these amino acids are generally activated by naturally occurring enzymes. The amino acid prodrugs improve oral delivery of drugs, which have poor permeability and solubility.
Two prodrugs 6a and 8a showed potent cytotoxcity, which is probably due to their high pept1 affinity and noreleasing ability. The selection of promoiety depends on the purpose of the prodrug. Tyagi 1 and arun gupta 2 1department of chemistry dav p. If even one essential or nonessential amino acid is absent, the remaining 19 cannot be used, and they become catabolized thus leading to a negative nitrogen. Three amino acid prodrugs were synthesized by conjugating isoleucine, tryptophan and methionine to lpv. Pdf although drugs currently used for the various types of diseases e. The development of prodrugs using amino acids as moieties has resulted in improvements in several properties, namely increased bioavailability, decreased toxicity of the parent drug, accurate delivery to target tissues or organs, and prevention of fast metabolism. In vitro evaluation of amino acid prodrugs of novel. An amino acid prodrug of the carboxylic acid drug can be synthesized by forming an amide between the amine of aminoacid and carboxylic acid of the drug. First, amino acid esters of ntx and ntxol were prepared in order to test their.
Institute of medicinal chemistry, school of pharmacy, university of lausanne, ch. The prodrug has the same utility as the drug from which it is made, but it has enhanced therapeutic properties. Enhanced absorption and growth inhibition with amino acid. Floxuridine fudr, 5fluoro2deoxyuridine is a fluori nated. Chemical and enzymatic stability of amino acid prodrugs. Request pdf amino acids as promoieties in prodrug design and development prodrugs are biologically inactive agents that upon biotransformation in vivo result in active drug molecules.
Pdf ocular pharmacokinetics of acyclovir amino acid. Prodrug formation was confirmed by the lcmsms and nmr technique. Essential amino acids, which generally have a longer halflife than the nonessential ones, are those that are required in the diet since the body cannot synthesize them in adequate amounts to maintain protein biosynthesis table 31. Phosphate and amino acid prodrugs of the hiv1 protease inhibitor pi atazanavir 1 were prepared and evaluated to address solubility and absorption limitations. The pharmacokinetics of dds, monoacetyldapsone madds. Thus, two classes of shpmpa and shpmpc prodrugs have been. Structure of 24aminophenylbenzothiazoles and their amino acid prodrugs. We hypothesized that amino acid ester prodrugs of bdcrb may enhance both in vitro potency and systemic exposure of bdcrb through evasion of bdcrbmetabolizing enzymes. In our study, this approach was employed in the rational drug design of novel aminoacidester prodrugs wscp117 to improve car solubility while retaining the antibacterial activity. Three amino acids probably explain the toxicity of some deadly chinese mushrooms. Specific role of amino acids as promoieties is explained with respect to transport mechanisms, pharmacokinetics and a low toxicity of compounds. Intestinal permeability studies of amino acid zanamivirs prodrugs compared to the parent drug confirmed that this targeted prodrug strategy.
Amino acid ester prodrugs of nucleoside and nucleotide antivirals volume. Interaction of intestinal nucleoside transporter hcnt2. In comparison to 29 and 30 and all prodrugs tested with exception of compound 33e had much lower activities. Synthesis, hydrolysis studies and phamacodynamic profiles of. Synthesis, characterization and pharmacological evaluation of. Synthesis of nsaid with sulfonamide conjugates as possible. The larger the score for a particular amino acid, the more likely the substitution is to occur. High tissue concenltrationls are achieved in the colonic mucosaandaccessgained toagreaterpartofthe colon thancanl beachieved byrectal administrationi. Ldopa crosses the bloodbrain barrier through ltype amino acid transporter1 and is metabolized by aromatic amino acid decarboxylase to active dopamine in the cns. The l amino acid esters were better prodrugs than the corresponding d or d, lisomers, suggesting the involvement of a stereoselective transporter. Prodrugs approach is a versatile approach in solving the problems associated with drug molecules. Modern prodrug design for targeted oral drug delivery mdpi. The amino acid prodrugs 33c, 33d, 33h, 33i, 33j and 33k demonstrated to be highly active against hbv and have a higher selective index than the parent drug 32. Examples of codrugs include sulfapyridine 5aminosalicylic acid, indomethacin.
Amino acids are biocompatible and easily ionisable. The present invention is directed to a prodrug comprised of an amino acid bonded to a medicament or drug having a hydroxy, amino, carboxy or acylating derivative thereon. Activation of amino acid prodrugs prodrug activation can occur chemically or enzymatically. Another example of a historical prodrug is aspirin acetylsalicylic acid, synthesized in 1897 by felix hoffman bayer, germany, and in troduced into medicine by dreser in 1899 12. Amino acid prodrugs for oral delivery should have high chemical stability in the gastrointestinal environment, but rapidly and quantitatively convert to parent drug prior to the systemic circulation. As shown in figure 2, s hpmpc 1, and s hpmpa 2, incorporate a hydroxymethylene function in their structure, which is able to esterify the anp phosphonic acid group intramolecularly, producing cyclic forms of the anps, chpmpc 3 and chpmpa 4. The importance of these transporters in pharmacokinetics. Ocular pharmacokinetics and efficacy of various amino acid and dipeptide prodrugs of ganciclovir sriram gunda, candidate for the doctor of philosophy degree university of missouri kansas city, 2012 abstract herpes simplex virus infections hsv in the eye are one of the leading causes of blindness across the world.