> Chemicals & Drugs > Chemical Viewed Functionally > Prodrugs

Prodrugs

Prodrugs are inactive compounds that are transformed into an active drug within the body.
This conversion can occur through metabolic processes, such as enzymatic hydrolysis or reduction.
Prodrugs are designed to improve the pharmacokinetic or physicochemical properties of a drug, enhancing its solubility, absorption, distribution, or stability.
They may also help to reduce side effects or target the drug to specific tissues or cell types.
Prodrugs are commonly used to improve the delivery of drugs that have poor bioavalibiliy or limited aqueous solubillity.
This description provides a concise overview of prodrugs and their applications in drug development.

Most cited protocols related to «Prodrugs»

Neurogenetics Study of Alcohol Use Disorder

Data were derived from 897 participants (513 women, mean age 19.62±1.24) who had successfully completed the ongoing Duke Neurogenetics Study (DNS) as of as of December 31, 2013. The DNS assesses a range of behavioral and biological traits among young adult, university students. The study was approved by the Duke University School of Medicine Institutional Review Board. All participants provided informed consent in accord with Duke University guidelines, and were in good general health. All participants were free of the following exclusionary criteria: (1) medical diagnoses of cancer, stroke, diabetes requiring insulin treatment, chronic kidney or liver disease, or lifetime history of psychotic symptoms; (2) use of psychotropic, glucocorticoid, or hypolipidemic medication; and (3) conditions affecting cerebral blood flow and metabolism (e.g., hypertension).
Our analyses focused on a subset of 759 participants (426 women, mean age 19.65±1.24) with BOLD fMRI data surviving a stringent multi-level quality control procedure (Supplementary Table 1). Of these 759 participants, 127 (55 women; mean age 19.79±1.21) met criteria for at least one current Axis I or select Axis II (borderline or antisocial personality disorder) diagnosis according to DSM-IV. The majority of these individuals (n=86; 35 women, mean age 19.94±1.15) were diagnosed with AUD (Supplementary Table 2). Since our study focuses on inter-individual variability in problem drinking, we did not exclude individuals with categorical disorders from analyses. Furthermore, we used presence of a current alcohol-related disorder (alcohol abuse or dependence) as a dependent variable in a subset of analyses. Notably, participants were required to pass a breathalyzer test before scanning to ensure they were not acutely intoxicated at the time of data collection. In addition, participants were asked to refrain from using any psychoactive substances while participating in the study and notified that they would be subject to a random drug screen on the day of their scan. Immediately preceding neuroimaging data collection, every 10^th male participant was asked to provide a urine sample, which was tested on a QuickScreen Pro Drug Screening test (Phamatech Inc, San Diego, CA) for the presence of amphetamine, methamphetamine, opiates, cocaine and tetrahydrocannabinol (THC). Due to the pharmacokinetics of THC,^{33 (link)} the presence of the chemical in urine was not deemed exclusionary unless the participant was acutely intoxicated. No participant was excluded for acute THC intoxication or tested positive for any other substance.

Nikolova Y.S., Knodt A.R., Radtke S.R, & Hariri A.R. (2015). Divergent responses of the amygdala and ventral striatum predict stress-related problem drinking in young adults: Possible differential markers of affective and impulsive pathways of risk for alcohol use disorder. Molecular psychiatry, 21(3), 348-356.

Publication 2015

Abuse, Alcohol Alcohol Related Disorders Amphetamines Antisocial Personality Disorder Biopharmaceuticals Breathalyzer Tests Cerebrovascular Accident Cerebrovascular Circulation Cocaine Diabetes Mellitus Dronabinol Drug Kinetics Epistropheus Ethics Committees, Research fMRI Glucocorticoids High Blood Pressures Hypolipidemic Agents Insulin Kidney Liver Diseases Males Malignant Neoplasms Mental Disorders Metabolism Methamphetamine Neurogenesis Opiate Alkaloids Pharmaceutical Preparations Prodrugs Psychotropic Drugs Radionuclide Imaging Student Substance Abuse Detection Urine Woman Young Adult

Neurogenetics Study of Alcohol Use Disorder

Publication 2015

Modeling Molecular Properties for Drug Design

The property calculators from three widely used molecular modeling
companies, Schrodinger/QikProp (QP) (http://www.schrodinger.com/products/14/17/), Tripos (TP) (http://www.tripos.com/index.php?family=modules,SimplePage,,,&page=sybyl_ligand_based_design), and Accelrys Pipeline Pilot (AP) Component Collections (http://www.accelrys.com/products/pipeline-pilot/component-collections.html), were used for calculating the various properties.
The SD
files containing the two-dimensional (2D) structures of the two classes
of drugs were subjected to the following steps.
Counterions
were removed, and the base structure was neutralized
where possible (except for quaternary ammonium salts) in AP.
2D structures were converted to 3D using Schrodinger/LigPrep. 3D
structures were used for property calculations in the three molecular
modeling packages listed above, even though some property calculators
require only the topological information.
Customized property
distribution curves were generated using internally
modified AP components, where each nonterminal column includes the
value where it was centered and anything less than the next bin. The
left terminal column also includes all points below the bin, and the
right terminal column includes all points higher than the last bin.
The “preferred” and “qualifying” property
ranges were determined using internally developed programs. The preferred
ranges were the shortest (most populated) property ranges covering
50% of the drugs. The qualifying ranges were the shortest (most populated)
property ranges covering 95% of the drugs. The preferred range is
a shorter range within the qualifying range. Because the population
density of approved drugs is considerably higher in the preferred
range than the population density in the qualifying range, compounds
satisfying the preferred range are expected to have a better survival
rate. The population density usually increases if the percentage of
drug coverage is lowered. However, decreasing the percentage of drug
coverage increases the chance of neglecting good compounds. Preferred
and qualifying ranges described here were a compromise between these
two opposing conditions. Should all approved drugs be considered to
derive the acceptable property ranges? Omitting 5% of the drugs would
help to neglect the outliers resulting from prodrugs or compounds
with active transport mechanisms, which are rare, but the properties
of such compounds are often well outside the more common range. The
95% ranges were fairly wide and would accommodate most compounds that
could be optimized within an acceptable time period. The preferred
range was a highly populated narrow band covering 50% of the approved
drugs, which would be used as a directional guide for future compound
design by moving the property closer to this range.
Qualitative
rules for CNS and non-CNS drugs were derived from the
properties whose distribution curves have different shapes or gradients.
The shape of a distribution curve depended on the location and size
of the bin. When distribution curves are generated, the data range
is rounded and the rounded range is divided into approximately 10
bins.
Several classification trees were derived to differentiate
between
CNS and non-CNS oral drugs. The most promising one was presented here.

Ghose A.K., Herbertz T., Hudkins R.L., Dorsey B.D, & Mallamo J.P. (2011). Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery. ACS Chemical Neuroscience, 3(1), 50-68.

Publication 2011

Biological Transport, Active Central Nervous System Agents Chloride, Ammonium Ligands Pharmaceutical Preparations Prodrugs Trees

Prodrug-Induced Cell Ablation in Zebrafish

Transgenic expression of the bacterial enzyme nitroreductase (nfsB, NTR) facilitates prodrug-inducible cell-type specific ablation in zebrafish [29] (link), [35] (link). Transgenic lines expressing NTR and a fluorescent reporter in specific cell types were used to determine whether ARQiv could detect the selective loss and regeneration of fluorescently labeled cells. Prior to cell ablation, NTR-expressing and control non-expressing larvae were scanned to determine pre-treatment fluorescence and background levels. Afterwards, larvae were treated for 24 hrs with media containing the prodrug metronidazole (MTZ, 10 mM for pancreatic beta cell ablation, 2.5 mM for rod photoreceptor cell ablation) to induce ablation of NTR-expressing cells, or with control media. After 24 hrs, all wells were rinsed three times and returned to control media. Subsequent post-treatment and recovery scans were performed at the indicated intervals. Confocal imaging was used to verify the loss and return of fluorescent reporters in the targeted cell types in identically treated subjects.

Walker S.L., Ariga J., Mathias J.R., Coothankandaswamy V., Xie X., Distel M., Köster R.W., Parsons M.J., Bhalla K.N., Saxena M.T, & Mumm J.S. (2012). Automated Reporter Quantification In Vivo: High-Throughput Screening Method for Reporter-Based Assays in Zebrafish. PLoS ONE, 7(1), e29916.

Publication 2012

Animals, Transgenic Bacteria Cells Enzymes Fluorescence Larva Metronidazole Nitroreductases Pancreatic beta Cells Prodrugs Radionuclide Imaging Regeneration Rod Photoreceptors Zebrafish

Corneal Transport Kinetics of Prodrugs

New Zealand, male, albino, rabbits were anesthetized using ketamine / xylazine administered intramuscularly and euthanized by injecting an overdose of pentobarbital into the marginal ear vein. Eyes were enucleated and were immediately washed with ice cold Dulbecco's Phosphate Buffered Saline (DPBS), pH 7.4, to remove any traces of blood. The corneas were excised immediately; with approximately 1 mm scleral portion remaining adhered to the cornea for ease of mounting. Corneas were mounted between standard, 9 mm, side-by-side diffusion cells (PermeGear Inc., Bethlehem, PA) with the epithelial layer facing the donor side. Temperature was maintained at 34 °C during the transport studies with the help of a circulating water bath. Volume of the receiver solution (3.2 mL DPBS) was slightly higher than that of the donor solution (3 mL drug solution) to maintain the natural curvature of the cornea. Drug solution was prepared in DPBS pH 5 ± 0.1 as the prodrugs were stable at this pH for the duration of the experiment (<1% hydrolyzed in 3 h). DPBS pH 7.4 was used as the receiver solution. Contents of both chambers were stirred continuously. Aliquots, 200 μL, were withdrawn at appropriate time intervals and immediately replaced with equal volume of DPBS and stored at −80 °C until further analysis.

Majumdar S., Hingorani T., Srirangam R., Gadepalli R.S., Rimoldi J.M, & Repka M.A. (2008). Transcorneal Permeation of L - and D - Aspartate Ester Prodrugs of Acyclovir: Delineation of Passive Diffusion versus Transporter Involvement. Pharmaceutical research, 26(5), 1261-1269.

Publication 2008

Albinism Bath BLOOD Cells Cold Temperature Cornea Diffusion Drug Overdose Eye Ketamine Males Oryctolagus cuniculus Pentobarbital Phosphates Prodrugs Saline Solution Sclera Tissue Donors Veins Xylazine

Most recents protocols related to «Prodrugs»

Purification of IL-2 Mutein Polymer Prodrug

Not available on PMC !

Example 6

Compound 3 was generated from the purification process of IL-2 mutein Ala-M1 polymer prodrug 5. During separation of compound 5 on a Capto MMC ImpRes resin the later eluting peak which contains 3 was collected. The collected fraction was diluted with 10 mM succinic acid, pH 5.0 to lower the conductivity to approx. 14 mS/cm and further purified on a Äkta system equipped with a HiScreen Capto Blue column using buffer A (20 mM sodium phosphate, pH 7.5), buffer B (20 mM sodium phosphate, 1 M NaCl, pH 7.5) and a gradient from 0 to 50% buffer B in 6 column volumes. The main peak was collected and concentrated using Amicon Ultra centrifugal device (3 kDa MWCO). The concentrated solution was buffer exchanged to 10 mM Hepes, 150 mM NaCl, 3 mM EDTA, 0.05% polysorbate 20, pH 7.4 by using an Äkta system and a HiPrep 26/10 column and the concentration was adjusted to 0.25 mg/mL to give compound 3.

US11879001B2. Conjugate comprising an IL-2 moiety (2024-01-23). ASCENDIS PHARMA ONCOLOGY DIVISION A/S [DK]. Inventors: Nina Gunnarsson [DK], Matiss Maleckis [DK], David B. Rosen [US].

Patent 2024

Buffers Edetic Acid Electric Conductivity HEPES interleukin-2, polyethylene glycol-modified Medical Devices mutein 2 mutein 5 Polymers Polysorbate 20 Prodrugs Resins, Plant Sodium Chloride sodium phosphate Succinic Acid

Bioactivity Validation of Compounds 3 and 7

Not available on PMC !

Example 19

To confirm bioactivity of 3 and 7, experiments were performed with the HH cell line, a mature T cell line derived from peripheral blood of a patient with aggressive cutaneous T cell leukemia/lymphoma (ATCC® CRL-2105™) which been demonstrated to only express the IL-2Rβ/γ. One of the earliest events in cytokine mediated activation of lymphocytes such as CD8+ T cells and NK cells is Janus Associated Kinase mediated phosphorylation and activation of Signal transducer and activator of transcription (pSTAT5). Thus, pSTAT5 was used to measure biological activity of 3 and 7 alongside 12. 3 demonstrated clear bioactivity in IL-2Rβ/γ expressing HH cells (EC₅₀: 773 ng/ml) that was approximately 3.5 fold lower than 12 (EC₅₀: 233 ng/ml). Additionally, 7 induced bioactivity (EC₅₀: 756 ng/ml) very similar to 3, demonstrating that 7 retains bioactivity after being released from prodrug 5 even after accelerated (stress) conditions.

US11879001B2. Conjugate comprising an IL-2 moiety (2024-01-23). ASCENDIS PHARMA ONCOLOGY DIVISION A/S [DK]. Inventors: Nina Gunnarsson [DK], Matiss Maleckis [DK], David B. Rosen [US].

Patent 2024

Biopharmaceuticals BLOOD CD8-Positive T-Lymphocytes Cell Lines Cells Cytokine IL19 protein, human Kinase, Janus Leukemia Lymphocyte Activation Lymphoma, T-Cell, Cutaneous Natural Killer Cells Patients Phosphorylation Prodrugs Transcription, Genetic Transducers

Targeted Paclitaxel Nanoparticle Cytotoxicity

Not available on PMC !

Example 5

2F2B mouse endothelial cells (ATCC, Manassas, Va., USA) were incubated for 2 days in media, upregulated with 10 nM nicotine or 10 μM angiotensin II to express α_vβ₃integrin. The cells may then be exposed to integrin-targeted versus nontargeted paclitaxel-GNB nanoparticle treatments with varying drug loads (0.5 to 5 mole %). The cells were also exposed to equivalent amounts of free drug for 30 minutes as a control. Unbound nanoparticles or unabsorbed drug was washed from wells, and cultures were grown for 6 days, and attached viable cell numbers were counted. The number of cells was significantly decreased when treated with paclitaxel-PC prodrug nanoparticles (PC-PTXL), versus equivalent amounts of free Taxol, α_vβ₃integrin-targeted nanoparticles alone, or saline (FIG. 9).

US11872313B2. Prodrug compositions, prodrug nanoparticles, and methods of use thereof (2024-01-16). Washington University [US]. Inventors: Gregory M. Lanza [US], Dipanjan Pan [US].

Patent 2024

130-nm albumin-bound paclitaxel Angiotensin II Cells Endothelial Cells Integrins Mus Nevus Nicotine Paclitaxel Pharmaceutical Preparations Prodrugs Saline Solution Taxol

Synthesis of Methotrexate Conjugates

Not available on PMC !

Example 7

The synthesis of the methotrexate conjugates is described in (FIG. 12). A short ethylene diamine spacer may be introduced between methotrexate and the oxidized lipid. 6-Bromomethyl-pteridine-2,4-diamine trihydrobromide (BPT.HBr, 23) may be purchased from Ube Industries and coupled with intermediate 24 to produce 25. Compound 25 may be deprotected from tert-Boc followed by ester hydrolysis to produce amine terminated methotrexate (26). Reductive amination of 26 with ALDO (PE) or (PC) may be performed as described earlier to produce methotrexate prodrugs (27).

US11872313B2. Prodrug compositions, prodrug nanoparticles, and methods of use thereof (2024-01-16). Washington University [US]. Inventors: Gregory M. Lanza [US], Dipanjan Pan [US].

Patent 2024

Amination Amines Anabolism Diamines Esters Ethylenediamines Hydrolysis Lipids Methotrexate Prodrugs Pteridines TERT protein, human

Synthesis of Platinum-Based Anti-Cancer Prodrugs

Not available on PMC !

Example 6

For the synthesis of platinum based anti cancer prodrugs, two approaches may be followed. The first approach (FIG. 10) may involve the preparation of an amine terminated cis platin (9) followed by conjugation with oxidized lipids. The coupling intermediate produced from the amidation reaction of compound 8 with mono Boc-ethylenediamine in presence of HATU/DIPEA, may be subjected to deprotection to produce compound 9. Compound 9 may undergo reductive amination with ALDO PC in methanol to generate cis platin prodrug-1 (10).

A second approach (FIG. 11) may involve the synthesis of an analogue bearing hydrophobically modified chelating diamines. Cis-platin intermediate 16 may be obtained in three steps from compound 13. Intermediate 16 may be subjected to complexation with K₂PtCl₄by maintaining the pH of the resulting solution at pH 6-7. Finally, compound 13 may undergo reductive amination with ALDO (PC) or (PE) to produce cis platin prodrug-2 (18).

US11872313B2. Prodrug compositions, prodrug nanoparticles, and methods of use thereof (2024-01-16). Washington University [US]. Inventors: Gregory M. Lanza [US], Dipanjan Pan [US].

Patent 2024

Amination Amines Anabolism CISH protein, human Cisplatin Diamines DIPEA Ethylenediamines Lipids Malignant Neoplasms Methanol Platinum Prodrugs SOCS2 protein, human

Top products related to «Prodrugs»

Dimethyl sulfoxide (dmso) by Merck Group

Sourced in United States, Germany, United Kingdom, China, Italy, Sao Tome and Principe, France, Macao, India, Canada, Switzerland, Japan, Australia, Spain, Poland, Belgium, Brazil, Czechia, Portugal, Austria, Denmark, Israel, Sweden, Ireland, Hungary, Mexico, Netherlands, Singapore, Indonesia, Slovakia, Cameroon, Norway, Thailand, Chile, Finland, Malaysia, Latvia, New Zealand, Hong Kong, Pakistan, Uruguay, Bangladesh

DMSO is a versatile organic solvent commonly used in laboratory settings. It has a high boiling point, low viscosity, and the ability to dissolve a wide range of polar and non-polar compounds. DMSO's core function is as a solvent, allowing for the effective dissolution and handling of various chemical substances during research and experimentation.

Facscalibur by BD

Sourced in United States, Germany, United Kingdom, China, Canada, Japan, Italy, France, Belgium, Switzerland, Singapore, Uruguay, Australia, Spain, Poland, India, Austria, Denmark, Netherlands, Jersey, Finland, Sweden

The FACSCalibur is a flow cytometry system designed for multi-parameter analysis of cells and other particles. It features a blue (488 nm) and a red (635 nm) laser for excitation of fluorescent dyes. The instrument is capable of detecting forward scatter, side scatter, and up to four fluorescent parameters simultaneously.

Raw blue cells by InvivoGen

Sourced in United States, France

RAW-Blue cells are a reporter cell line derived from the RAW 264.7 murine macrophage cell line. They stably express a secreted embryonic alkaline phosphatase (SEAP) gene under the control of a NF-κB-inducible promoter. These cells can be used to monitor NF-κB activation in response to various stimuli.

Quanti blue assay by InvivoGen

Sourced in United States

QUANTI-Blue assay is a colorimetric assay used to detect and quantify alkaline phosphatase (AP) activity. It provides a simple and sensitive way to measure AP levels in cell culture supernatants, bacterial cultures, or other samples.

Prism 9 by GraphPad

Sourced in United States, Austria, Germany, Poland, United Kingdom, Canada, Japan, Belgium, China, Lao People's Democratic Republic, France

Prism 9 is a powerful data analysis and graphing software developed by GraphPad. It provides a suite of tools for organizing, analyzing, and visualizing scientific data. Prism 9 offers a range of analysis methods, including curve fitting, statistical tests, and data transformation, to help researchers and scientists interpret their data effectively.

Fetal bovine serum (fbs) by Thermo Fisher Scientific

Sourced in United States, China, United Kingdom, Germany, Australia, Japan, Canada, Italy, France, Switzerland, New Zealand, Brazil, Belgium, India, Spain, Israel, Austria, Poland, Ireland, Sweden, Macao, Netherlands, Denmark, Cameroon, Singapore, Portugal, Argentina, Holy See (Vatican City State), Morocco, Uruguay, Mexico, Thailand, Sao Tome and Principe, Hungary, Panama, Hong Kong, Norway, United Arab Emirates, Czechia, Russian Federation, Chile, Moldova, Republic of, Gabon, Palestine, State of, Saudi Arabia, Senegal

Fetal Bovine Serum (FBS) is a cell culture supplement derived from the blood of bovine fetuses. FBS provides a source of proteins, growth factors, and other components that support the growth and maintenance of various cell types in in vitro cell culture applications.

Microplate reader by Thermo Fisher Scientific

Sourced in United States, China, Finland, Germany, Japan, United Kingdom, Spain, France, Italy, Australia, Sweden, Singapore, Canada, India, Denmark

The Microplate reader is a laboratory instrument designed to measure the absorbance, fluorescence, or luminescence of samples in a microplate format. It is a versatile tool used in various applications, such as enzyme-linked immunosorbent assays (ELISAs), cell-based assays, and drug discovery screens.

Tcs sp2 aobs by Leica

Sourced in Germany, United Kingdom, Japan, United States

The TCS SP2 AOBS is a confocal laser scanning microscope produced by Leica. It is designed for high-resolution fluorescence imaging and features an acousto-optical beam splitter (AOBS) for flexible control of laser lines. The TCS SP2 AOBS provides researchers with a powerful tool for advanced microscopy applications.

Zetasizer nano z by Malvern Panalytical

Sourced in United Kingdom, Germany, United States, France, Japan, China, Netherlands, Morocco, Spain, Cameroon

The Zetasizer Nano ZS is a dynamic light scattering (DLS) instrument designed to measure the size and zeta potential of particles and molecules in a sample. The instrument uses laser light to measure the Brownian motion of the particles, which is then used to calculate their size and zeta potential.

1200 series by Agilent Technologies

Sourced in United States, Germany, United Kingdom, Switzerland, France, Belgium, Spain

The Agilent 1200 series is a line of high-performance liquid chromatography (HPLC) instruments designed for analytical and preparative applications. The core function of the 1200 series is to provide precise and reliable separation, detection, and quantification of chemical compounds in complex mixtures.

More about "Prodrugs"

Prodrugs are inactive pharmaceutical compounds that are designed to be transformed into their active form within the body.
This conversion process can occur through various metabolic pathways, such as enzymatic hydrolysis or reduction.
Prodrugs are commonly used to improve the delivery and efficacy of drugs that have poor bioavailability or limited aqueous solubility.
The utilization of prodrugs can enhance a drug's pharmacokinetic or physicochemical properties, including its solubility, absorption, distribution, or stability.
This approach may also help to reduce unwanted side effects or target the active compound to specific tissues or cell types.
Prodrugs are particularly beneficial for drugs that struggle with issues like poor absorption, rapid metabolism, or undesirable distribution patterns.
Some key applications of prodrugs include improving the delivery of drugs with limited aqueous solubility, enhancing the stability of labile compounds, and selectively targeting the active drug to a specific site of action.
Prodrug strategies can be employed across a wide range of therapeutic areas, from small molecule pharmaceuticals to biological drugs like peptides and proteins.
When researching prodrugs, researchers may utilize various analytical techniques and tools, such as DMSO for solubility studies, FACSCalibur for cell-based assays, RAW-Blue cells and QUANTI-Blue assays for evaluating biological activity, Prism 9 for data analysis, and microplate readers for high-throughput screening.
Specialized instrumentation like the TCS SP2 AOBS confocal microscope and Zetasizer Nano ZS for particle sizing can also contribute to prodrug development and characterization.
By leveraging the insights provided by the MeSH term description and the Metadescription, researchers can optimze their prodrug research and development efforts, identifying the most effective protocols and prodrug candidates to advance their projects.
The PubCompare.ai platform can be a valuable tool in this process, enabling efficient literature searches, protocol comparisons, and data-driven decision making.