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ProdrugsHydrolysisEstersKineticsDrug StabilityAdenosine TriphosphateMolecular StructureSubstrate SpecificityBiotransformationCarboxylic Ester HydrolasesChromatography, High Pressure LiquidDipeptidesAniline MustardAmpyroneDrug DesignHydrogen-Ion ConcentrationCarboxylesteraseFloxuridineDrug Delivery SystemsCaco-2 CellsAcyclovirgamma-Glutamyl HydrolaseAdenosine TriphosphatasesNucleosidesCatalysisOrganophosphonatesStereoisomerismPhosphatidylinositolsSolubilityChemistry Techniques, SyntheticEsterasesGuanosine TriphosphateStructure-Activity RelationshipSulfadimethoxineBiopharmaceuticsMolecular Sequence DataBinding SitesModels, MolecularSulfamerazineBiological AvailabilityEscherichia coliAdenineMagnetic Resonance SpectroscopyNitroreductasesPhosphoramide MustardsAntiviral AgentsPhosphoric AcidsInhibitory Concentration 50Organophosphorus CompoundsNitrophenolsAmino Acid SequenceAdenosine DiphosphateEnkephalin, Leucine-2-AlanineAmino AcidsDrug Screening Assays, AntitumorBromouracilPharmaceutic AidsAntineoplastic AgentsProtein Binding
EsterEnzyme mediated hydrolysisSuccessful prodrug designEnzymaticUndergoesSynthesisAbsorptionEnalaprilatCompoundsAmino acidVitroPharmacologically inactiveMetabolismPhysicochemicalSolubilityLiverInactiveDerivativesAssayIntestinalMoleculesOxidationKineticsVivoDegradationCandesartanEnzymesDissolutionDabigatranOralDrugMolecular mechanicsYieldRapidlyDesignActivationStudyRateStabilityApproachFormationDrugsDevelopmentExamplesHumanRelease
Ester12
  • following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin-converting enzyme inhibitor. (rxlist.com)
  • In our group we have been developing with success ester prodrugs of pyrazinoic acid that addressed efficiently pyrazinamide resistance in M. tuberculosis, and small molecules with dual stage activity for blood and liver stages of malaria. (ulisboa.pt)
  • The derivatives were reconverted to the parent compound (Cur) after cleavage of the ester bonds by microsomal esterase, indicating that the compounds could act as Cur prodrugs. (researchgate.net)
  • Conclusions The cationic N,N-dimethyl amino acid ester prodrugs of Cur improved the water solubility of Cur and enhanced oral bioavailability in rats. (researchgate.net)
  • Further, no correlation was found between the active parent drug's release and the distance between the nucleophile and the electrophile in the dicarboxylic semi-ester (atovaquone prodrug). (alquds.edu)
  • Using the half time needed for the interconversion of 50% of di-carboxylic semi-ester 1 and the calculated log krel values for the designed atovaquone prodrugs the t1/2 values for interconversion of those prodrugs to their active parent drug were calculated. (alquds.edu)
  • ester/amide is definitely then triggered through hydrolysis or oxidation and the active drug moiety is definitely liberated. (mycareerpeer.com)
  • Levonorgestrel butanoate (LB) serves as a pro-drug to deliver Levonorgestrel (LNG) to serum after hydrolysis of the ester. (nih.gov)
  • A prodrug approach for local and sustained diclofenac action after injection into joints based on ester prodrugs having a pH-dependent solubility is presented. (ku.dk)
  • Inherent ester prodrug properties influencing the duration of action include their pH-dependent solubility and charge state, as well as susceptibility to undergo esterase facilitated hydrolysis. (ku.dk)
  • In this study, physicochemical properties and pH rate profiles of 3 diclofenac ester prodrugs differing with respect to the spacer carbon chain length between the drug and the imidazole-based promoiety were determined and a rate equation for prodrug degradation in aqueous solution in the pH range 1-10 was derived. (ku.dk)
  • By hydrolysis of the carboxylate ester by either of the enzymes cathepsin A or carboxylesterase 1, Sofosbuvir is activated in the liver to the triphosphate GS-461203 followed by cleaving of the phosphoramidate by the enzyme histidine triad nucleotide-binding protein 1 (HINT1), along with repeated phosphorylation. (magicinepharma.com)
Enzyme mediated hydrolysis2
  • Olmesartan and candesartan were formed in S9 fraction in high rate, but not in buffer: indicating enzyme mediated hydrolysis. (helsinki.fi)
  • Prodrug activation can be achieved through enzyme-mediated hydrolysis or oxidation/reduction processes or through LY2835219 kinase activity assay chemical degradation within the body, triggered via a particular stimulus. (mycareerpeer.com)
Successful prodrug design2
  • Properties and selection of carriers or promoeities is a very important parameter in successful prodrug design. (ijpsonline.com)
  • The crucial step in the successful prodrug design is the inclusion of the activation mechanism that releases an active parent drug from a prodrug molecule in an efficient/controlled way, in order to accomplish a successful restorative effect. (mycareerpeer.com)
Enzymatic6
  • Prodrugs are derivatives of drug molecules that are pharmacologically inactive but require either chemical or enzymatic transformation to release the active drug in vivo in order to exert a pharmacological effect. (ijpsonline.com)
  • These prodrugs subsequently undergo enzymatic or non-enzymatic cleavage to release the active drug moiety (figure 1) [ 12 , 13 ]. (ijpsonline.com)
  • Intro Prodrug is definitely a drug derivative intended to undergo chemical/enzymatic activation and therefore release an active parent drug, which is definitely then free to accomplish its pharmacological effect in the body [1]. (mycareerpeer.com)
  • In addition, several in silico techniques are employed in the optimization of the prodrug structure or prodrug-enzyme LY2835219 kinase activity assay complex, in order to facilitate enzymatic cleavage. (mycareerpeer.com)
  • It is an inactive prodrug which undergoes enzymatic hydrolysis in the liver to for its active metabolite, desglymidodrine. (eddyjoemd.com)
  • The prodrug degradation was found to be about 6-fold faster in 80% (vol/vol) human plasma as compared to 80% (vol/vol) human synovial fluid with 2-(1-methyl-1H-imidazol-2-yl)ethyl 2-(2-(2,6 dichlorophenyl)amino)phenylacetate being the poorest substrate toward enzymatic cleavage. (ku.dk)
Undergoes1
  • Undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. (medscape.com)
Synthesis3
  • Though several studies have been carried out on various prodrugs, surprisingly very few reviews on different carriers, which can be used for prodrug synthesis were published to date. (ijpsonline.com)
  • In this review different types of carriers, which can be used for prodrug synthesis are summarized. (ijpsonline.com)
  • The objective of this review is to provide the researchers with a compilation of which carriers would be suitable for prodrug synthesis and what would be their benefits. (ijpsonline.com)
Absorption4
  • The Cur prodrugs enhanced the absolute oral bioavailability of Cur by a 9- and threefold increase of suspended and dissolved Cur administration, respectively, thereby improving intestinal absorption. (researchgate.net)
  • Prodrugs have been designed to improve so called drug-like properties of active parent compounds (APC) i.e. to increase solubility or absorption and to reduce first-pass metabolism etc. (helsinki.fi)
  • Prodrugs constitute a particularly useful approach for altering physicochemical drug properties (e.g., solubility) and for optimizing drug-like features of active compounds (we.e., absorption, distribution, rate of metabolism and excretion (ADME)) [5,6]. (mycareerpeer.com)
  • Such prodrugs were often designed to enhance oral drug absorption [10]. (mycareerpeer.com)
Enalaprilat2
  • Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. (nih.gov)
  • Enalapril belongs to prodrugs: after its hydrolysis, enalaprilat is formed in the body, which inhibits this enzyme. (bestpharmbuy.com)
Compounds2
  • The prodrug strategy implementation in the last 20 y has led to a steady advancement in the biopharmaceutical, physicochemical and/or pharmacokinetic attributes of the pharmacologically active compounds. (ijpsonline.com)
  • Four commercially available prodrugs (bambuterol, olmesartan medoxomil (OM), candesartan cilexetil (CC) and famciclovir) were used as test compounds. (helsinki.fi)
Amino acid1
Vitro7
  • In this master's thesis the goal was to establish non-cell-based in vitro methods to study prodrug bioactivation. (helsinki.fi)
  • The prodrugs were incubated in liver and intestinal S9 fractions and blood plasma to study in vitro bioactivation of these prodrugs. (helsinki.fi)
  • The in vitro incubation used in this study can be used for screening prodrugs. (helsinki.fi)
  • the carboxylesterase-mediated rate of metabolism of DABE and the result of alcohol around the hydrolysis of the traditional carboxylesterase substrate (cocaine) had been analyzed to validate the in vitro model. (gasyblog.com)
  • In vitro hydrolysis of DABE TEMPOL in HLS9. (gasyblog.com)
  • In vitro evaluation of the impact of Covid-19 therapeutic agents on the hydrolysis of the antiviral prodrug remdesivir. (cdc.gov)
  • The conversion and release of parent diclofenac from prodrug suspensions in vitro were studied using the rotating dialysis model. (ku.dk)
Pharmacologically inactive1
  • Prodrugs are pharmacologically inactive molecules which undergo metabolic bioactivation in vivo to form pharmaceutically active agents. (helsinki.fi)
Metabolism3
  • Hydrolysis in Drug and Prodrug Metabolism. (wikipedia.org)
  • Other metabolism of the prodrug and APC (nonproductive metabolism) was studied by comparing incubation with and without cofactors of metabolizing enzymes. (helsinki.fi)
  • prodrug (losartan, paclitaxel derivatives) rate of metabolism via CYP450 enzyme are offered, as well as an MD simulation for optimizing linker size in phospholipid-based prodrugs. (mycareerpeer.com)
Physicochemical1
  • Carrier-linked prodrugs are for drugs with major drawbacks, which are linked to a nontoxic carrier or promoiety through covalent linkage to change or get rid of their undesirable physicochemical properties. (ijpsonline.com)
Solubility1
Liver1
Inactive1
  • An inactive or weakly active substance that has an active metabolite is called a prodrug, especially if designed to deliver the active moiety more effectively. (msdmanuals.com)
Derivatives1
  • We have prepared derivatives of erythromycin B as putative paediatric prodrugs, taking advantage of the much improved acid stability of erythromycin B relative to erythromycin A. Thus, erythromycin B enol ether ethyl succinate is very poorly soluble in water, and its hydrolysis is undetectable in conditions resembling the medicine bottle. (nih.gov)
Assay2
  • In the mouse acetic acid induced writhing assay, the prodrugs exhibited, following acute administration, a good analgesic activity. (unict.it)
  • The prodrug approach has been proven efficacious for a number of restorative areas, including anticancer, anti-inflammatory, antiviral providers and angiotensin-converting LY2835219 kinase activity assay enzyme inhibitors (ACEI) [7]. (mycareerpeer.com)
Intestinal2
  • Dabigatran etexilate is a double prodrug that is hydrolyzed to the active dabigatran by intestinal and hepatic carboxylesterases. (drugbank.com)
  • However, based on literature CC hydrolysis was not expected to occur in intestinal S9 fractions. (helsinki.fi)
Molecules2
  • The main obstacle with these molecules is the lack of ability to foresee the bioconversion of the prodrug to the active parent drug, and thus its restorative effect. (mycareerpeer.com)
  • This can be overcome by using novel computational modeling techniques, which can improve the prodrug design of drug molecules with hydroxyl/phenol/amine practical groups [11]. (mycareerpeer.com)
Oxidation1
  • A bioprecursor prodrug is transformed chemically through hydration (for example, lactones such as some statins), reduction (for example, sulindac, platinum (IV) complexes) or oxidation (for example, dexpanthenol, nabumetone) or metabolically to the active agent [ 5 , 9 - 11 ]. (ijpsonline.com)
Kinetics1
Vivo2
Degradation1
  • In the pH range 6-10, the prodrugs were subject to parallel degradation to yield diclofenac and an indolinone derivative. (ku.dk)
Candesartan1
Enzymes2
  • To identify the precise enzymes in charge of DABE hydrolysis, distinct incubations using recombinant CES1 and CES2 had been conducted. (gasyblog.com)
  • The addition of the carboxylesterase inhibitor BNPP didn't affect this technique, suggesting how the gradual hydrolysis of DABE in individual plasma was spontaneous or mediated by various other enzymes. (gasyblog.com)
Dissolution6
  • A dynamic analysis of the dissolution and subsequent hydrolysis of aspirin has been determined by in-situ FT-IR. (shu.edu)
  • The data shows dissolution of aspirin with the hydrolysis profile and the formation of salicylic acid. (shu.edu)
  • Dissolution and hydrolysis of enteric coated aspirin tablets has been performed, and compared with the Bayer aspirin tablets. (shu.edu)
  • This technique indicates a future potential for real-time studies of dissolution and hydrolysis of other prodrugs such as Loratadine. (shu.edu)
  • One more demonstration of the in-situ FT-IR novel technique is the dissolution study of Loratadine (hydrolysis of Loratadine), a pro-drug that has a tendency to hydrolyze to an active compound desloratadine. (shu.edu)
  • The results suggest that it is possible to alter and control dissolution and reconversion behavior of the diclofenac prodrugs, thus making the prodrug approach feasible for local and sustained diclofenac action after joint injection. (ku.dk)
Dabigatran2
  • Dabigatran etexilate is an oral prodrug that is hydrolyzed to the competitive and reversible direct thrombin inhibitor dabigatran . (drugbank.com)
  • Dabigatran etexilate (DABE) can be an dental prodrug that's rapidly changed into the dynamic thrombin inhibitor, dabigatran (DAB), by serine esterases. (gasyblog.com)
Oral1
  • Sofosbuvir is a prodrug of the Protide type, whereby the active phosphorylated nucleotide is granted with cell permeability and oral bioavailability. (magicinepharma.com)
Drug3
  • The prodrug approach using various carriers has evolved as a significant tool in surmounting different obstacles in relation to drug formulation and targeting. (ijpsonline.com)
  • Prodrugs have better delivery properties that surpass the parent drug molecule [ 1 ]. (ijpsonline.com)
  • Prodrug concept is justified because it enables the active drug to overcome the barrier that would impede it from reaching the site of action to exert the required pharmacological activity. (ijpsonline.com)
Molecular mechanics1
  • Using DFT molecular orbital at B3LYP 6-31G (d,p) and B3LYP/311+G (d,p) levels and molecular mechanics (MM2) calculations of the hydrolysis of Bruice's di-carboxylic semi-esters 1-5 several atovaquone prodrugs were designed. (alquds.edu)
Yield1
  • Using fed-batch fermentation of FJ-PYC, we obtained the highest PMA titers (81.5, 94.2 g/L of MA after hydrolysis) in 140 h with a corresponding MA yield of 0.62 g/g and productivity of 0.67 g/L h. (biomedcentral.com)
Rapidly1
  • The prodrug approach is rapidly becoming a crucial part in the stratagem of delivery of drugs. (ijpsonline.com)
Design2
  • Utilizing the information gained from the prodrugs design, atovaquone ProD 1 was synthesized and fully characterized. (alquds.edu)
  • Computational simulations provide an important insight into the prodrug design and overall fitted of the prodrug to the enzyme catalytical site, consequently they should be carried out prior to experimental studies, in order to reduce cost and improve the efficiency of the prodrug development process. (mycareerpeer.com)
Activation3
  • Activation of benzoate model prodrugs by mycobacteria. (ulisboa.pt)
  • Valente E, Testa B, Constantino L. Activation of benzoate model prodrugs by mycobacteria. (ulisboa.pt)
  • This work focuses on the enzyme-mediated prodrug activation and optimization of this process through in silico methods. (mycareerpeer.com)
Study2
  • Prodrug concentrations were quantified from the incubation samples using liquid chromatography- tandem mass spectrometry (LC-MSMS) methods developed for this study. (helsinki.fi)
  • While the study was inconclusive, the incomplete hydrolysis of glycerol phenylbutyrate cannot be ruled out. (clustermed.info)
Rate3
  • Unfortunately, the prodrug hydrolyzes at a measurable rate in the medicine bottle, leading to the vile-tasting erythromycin. (nih.gov)
  • Studying the rate of prodrug formation alone estimations about clinically relevant bioactivation rates cannot be concluded. (helsinki.fi)
  • It was found that the interconversion rate of the designed atovaquone prodrugs is largely determined on the strain energies of the reaction's tetrahedral intermediates and reactants. (alquds.edu)
Stability1
  • All the prodrugs showed a good stability both in pH 7.4 phosphate buffer and in pH 2.0 buffer, and they were readily hydrolyzed by rat plasma. (unict.it)
Approach3
  • The success of the prodrug approach can be measured by examining how many prodrugs are currently on the market. (ijpsonline.com)
  • The main principle of the prodrug approach is definitely illustrated in Number 1. (mycareerpeer.com)
  • Open in a separate window Number 1 Illustration of the prodrug approach concept. (mycareerpeer.com)
Formation1
  • Nevertheless, it was shown earlier in the text that PON1 catalyzes the formation and hydrolysis of different kinds of lactones. (biochemia-medica.com)
Drugs1
  • Around 10 % of marketed medicines can be categorized as prodrugs currently, and also that during 2008, 33 % of approved small molecular weight drugs were prodrugs [ 5 - 7 ]. (ijpsonline.com)
Development1
  • Overall, high quality computational simulations may display good agreement with experimental results, and should be used early in the prodrug development process. (mycareerpeer.com)
Examples1
  • Examples of both marketed and investigational prodrugs using several promoieties are discussed with their advantages and future prospects. (ijpsonline.com)
Human1
Release1
  • Acid hydrolysis of PMA, resulting in release of the monomer l -malic acid (MA), which is widely used in the food and chemical industry, is a competitive process for producing bio-based platform chemicals. (biomedcentral.com)