Prodrugs: from Design to Clinic

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (15 January 2014) | Viewed by 72702

Special Issue Editors


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Guest Editor
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
Interests: prodrugs; CNS drug delivery; drug transporters
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Co-Guest Editor
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O.Box 1627, FI-70211 Kuopio, Finland
Interests: transporter; solute carriers (SLC); ATP-binding cassette (ABC); drug delivery; drug targeting; ADME; pharmacokinetics; toxicokinetics; drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We would like to invite you to submit an original manuscript, communication or review for this special issue. Your contribution to this topic will greatly enhance the understanding of this important topic to the readers of Pharmaceuticals. We would like the focus of this issue to be on the structure-activity relationships between promoiety structure and absorption, targeting and/or activation. Additional focus on the physicochemical changes that the prodrug moiety adds to the molecule and how that results in different PK, distribution kinetics and toxicities are also welcome.

Prof. Dr. Jarkko Rautio
Dr. Kristiina Huttunen
Guest Editor

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Keywords

  • prodrugs
  • bioprecursor
  • bioconversion

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Published Papers (7 papers)

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Research

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1903 KiB  
Article
Conformational Analysis, Molecular Structure and Solid State Simulation of the Antiviral Drug Acyclovir (Zovirax) Using Density Functional Theory Methods
by Margarita Clara Alvarez-Ros and Mauricio Alcolea Palafox
Pharmaceuticals 2014, 7(6), 695-722; https://doi.org/10.3390/ph7060695 - 6 Jun 2014
Cited by 16 | Viewed by 10728
Abstract
The five tautomers of the drug acyclovir (ACV) were determined and optimised at the MP2 and B3LYP quantum chemical levels of theory. The stability of the tautomers was correlated with different parameters. On the most stable tautomer N1 was carried out a comprehensive [...] Read more.
The five tautomers of the drug acyclovir (ACV) were determined and optimised at the MP2 and B3LYP quantum chemical levels of theory. The stability of the tautomers was correlated with different parameters. On the most stable tautomer N1 was carried out a comprehensive conformational analysis, and the whole conformational parameters (R, β, Φ, φ1, φ2, φ3, φ4, φ5) were studied as well as the NBO Natural atomic charges. The calculations were carried out with full relaxation of all geometrical parameters. The search located at least 78 stable structures within 8.5 kcal/mol electronic energy range of the global minimum, and classified in two groups according to the positive or negative value of the torsional angle j1. In the nitrogen atoms and in the O2' and O5' oxygen atoms of the most stable conformer appear a higher reactivity than in the natural nucleoside deoxyguanosine. The solid state was simulated through a dimer and tetramer forms and the structural parameters were compared with the X-ray crystal data available. Several general conclusions were emphasized. Full article
(This article belongs to the Special Issue Prodrugs: from Design to Clinic)
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Article
Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug
by Paul Matthew O'Byrne, Robert Williams, John J. Walsh and John F. Gilmer
Pharmaceuticals 2014, 7(6), 676-694; https://doi.org/10.3390/ph7060676 - 28 May 2014
Cited by 2 | Viewed by 10740
Abstract
N-methylbupropion was selected as a potential prodrug from our in vitro screening of analogues of bupropion described in the preceding paper. This study describes in vivo pharmacokinetics of N-methylbupropion in the guinea-pig animal model, which is reported to best predict human [...] Read more.
N-methylbupropion was selected as a potential prodrug from our in vitro screening of analogues of bupropion described in the preceding paper. This study describes in vivo pharmacokinetics of N-methylbupropion in the guinea-pig animal model, which is reported to best predict human metabolism of bupropion. The suitability of the guinea pig was established by studying N-demethylation of N-methylbupropion using S9 liver fractions. An LC-MS method was developed and validated to measure N-methylbupropion, bupropion and their metabolites in plasma and brain tissue. In separate studies, the prodrug was delivered by intraperitoneal injection (IP) to assess hepatic metabolism and then by oral gavage (PO) to assess the contribution from intestinal enzymes. Bupropion was administered in parallel. The pharmacokinetic profile of bupropion and N-methylbupropion were not comparable when dosed by intraperitoneal injection but when dosed orally, N-methylbupropion showed a comparable bupropion and metabolite PK plasma profile to bupropion. Plasma and brain levels of N-methylbupropion show that it is extensively metabolized to bupropion and its metabolites, and N-methyl-threo-hydrobupropion. This data coupled to the reduced DAT and NET system in vitro activity described in paper 1 would suggest that the N-methyl derivative of bupropion may have potential as an oral prodrug of bupropion in humans. Full article
(This article belongs to the Special Issue Prodrugs: from Design to Clinic)
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Article
Synthesis, Screening and Pharmacokinetic Evaluation of Potential Prodrugs of Bupropion. Part One: In Vitro Development
by Paul Matthew O'Byrne, Robert Williams, John J. Walsh and John F. Gilmer
Pharmaceuticals 2014, 7(5), 595-620; https://doi.org/10.3390/ph7050595 - 14 May 2014
Cited by 11 | Viewed by 10015
Abstract
In general, prodrugs are developed to circumvent deficiencies associated with the absorption, distribution, metabolism, excretion or toxicological (ADMET) profile associated with the active drug. In our study, we select bupropion, a drug with broad pharmacology incorporating dopaminergic, noradrenergic, nicotinic and cytokine modulation properties, [...] Read more.
In general, prodrugs are developed to circumvent deficiencies associated with the absorption, distribution, metabolism, excretion or toxicological (ADMET) profile associated with the active drug. In our study, we select bupropion, a drug with broad pharmacology incorporating dopaminergic, noradrenergic, nicotinic and cytokine modulation properties, but which is rapidly metabolized in vivo. we exploited its carbonyl and secondary amine functionality to facilitate the synthesis of bioprecursor prodrug forms with the sole objective of identifying analogues with enhanced properties over bupropion. A range of analogues were synthesized, ranging from N-methyl, N-benzyl, oximes, enol acetate and ether forms to examples where both functional groups were utilized to form oxadiazine, oxadiazinone, oxazolone and acetylated derivatives. we then developed an in vitro metabolic screen to simulate the human oral delivery route for these analogues. The selection of media in the screens contained a variety of pH, enzymatic and co-factor systems which mimic metabolic in vivo environments that drugs encounter when delivered orally. By coupling our in vitro screening tool to a selective hyphenated technique such as LC-MS, we were able to quickly select potential prodrugs for further in vitro and in vivo development. From the data generated, the N-alkylated bupropion analogues were shown to have the highest potential to act as bioprecursor prodrugs of bupropion. Full article
(This article belongs to the Special Issue Prodrugs: from Design to Clinic)
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Article
Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir
by Mitesh Patel, Nanda Mandava, Mitan Gokulgandhi, Dhananjay Pal and Ashim K. Mitra
Pharmaceuticals 2014, 7(4), 433-452; https://doi.org/10.3390/ph7040433 - 10 Apr 2014
Cited by 19 | Viewed by 7375
Abstract
Poor systemic concentrations of lopinavir (LPV) following oral administration occur due to high cellular efflux by P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) and extensive metabolism by CYP3A4 enzymes. In this study, amino acid prodrugs of LPV were designed and investigated for their [...] Read more.
Poor systemic concentrations of lopinavir (LPV) following oral administration occur due to high cellular efflux by P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) and extensive metabolism by CYP3A4 enzymes. In this study, amino acid prodrugs of LPV were designed and investigated for their potential to circumvent efflux processes and first pass effects. Three amino acid prodrugs were synthesized by conjugating isoleucine, tryptophan and methionine to LPV. Prodrug formation was confirmed by the LCMS/MS and NMR technique. Interaction of LPV prodrugs with efflux proteins were carried out in P-gp (MDCK-MDR1) and MRP2 (MDCK-MRP2) transfected cells. Aqueous solubility studies demonstrated that prodrugs generate higher solubility relative to LPV. Prodrugs displayed higher stability under acidic conditions and degraded significantly with rise in pH. Uptake and transport data suggested that prodrugs carry significantly lower affinity towards P-gp and MRP2 relative to LPV. Moreover, prodrugs exhibited higher liver microsomal stability relative to LPV. Hence, amino acid prodrug modification might be a viable approach for enhancing LPV absorption across intestinal epithelial and brain endothelial cells which expresses high levels of P-gp and MRP2. Full article
(This article belongs to the Special Issue Prodrugs: from Design to Clinic)
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Article
Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization
by Rebecca Nofsinger, Sophie-Dorothee Clas, Rosa I. Sanchez, Abbas Walji, Kimberly Manser, Becky Nissley, Jaume Balsells, Amrithraj Nair, Qun Dang, David Jonathan Bennett, Michael Hafey, Junying Wang, John Higgins, Allen Templeton, Paul Coleman, Jay Grobler, Ronald Smith and Yunhui Wu
Pharmaceuticals 2014, 7(2), 207-219; https://doi.org/10.3390/ph7020207 - 24 Feb 2014
Cited by 15 | Viewed by 10490
Abstract
Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to [...] Read more.
Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to enhance the colonic absorption of a drug molecule with a short half-life via a prodrug approach to deliver sustained plasma exposure and enable once daily (QD) dosing. The compound has poor absorption in the colon and by the addition of a promoiety to block the ionization of the molecule as well as increase lipophilicity, the relative colonic absorption increased from 9% to 40% in the retrograde dog colonic model. A combination of acceptable solubility and stability in the gastrointestinal tract (GI) as well as permeability was used to select suitable prodrugs to optimize colonic absorption. Full article
(This article belongs to the Special Issue Prodrugs: from Design to Clinic)
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Article
The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs
by Yasuhiro Tsume, Blanca Borras Bermejo and Gordon L. Amidon
Pharmaceuticals 2014, 7(2), 169-191; https://doi.org/10.3390/ph7020169 - 27 Jan 2014
Cited by 11 | Viewed by 8502
Abstract
Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their [...] Read more.
Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents. Full article
(This article belongs to the Special Issue Prodrugs: from Design to Clinic)
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Review

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2242 KiB  
Review
The Medicinal Chemistry of Imidazotetrazine Prodrugs
by Catherine L. Moody and Richard T. Wheelhouse
Pharmaceuticals 2014, 7(7), 797-838; https://doi.org/10.3390/ph7070797 - 10 Jul 2014
Cited by 57 | Viewed by 13780
Abstract
Temozolomide (TMZ) is the standard first line treatment for malignant glioma, reaching “blockbuster” status in 2010, yet it remains the only drug in its class. The main constraints on the clinical effectiveness of TMZ therapy are its requirement for active DNA mismatch repair [...] Read more.
Temozolomide (TMZ) is the standard first line treatment for malignant glioma, reaching “blockbuster” status in 2010, yet it remains the only drug in its class. The main constraints on the clinical effectiveness of TMZ therapy are its requirement for active DNA mismatch repair (MMR) proteins for activity, and inherent resistance through O6-methyl guanine-DNA methyl transferase (MGMT) activity. Moreover, acquired resistance, due to MMR mutation, results in aggressive TMZ-resistant tumour regrowth following good initial responses. Much of the attraction in TMZ as a drug lies in its PK/PD properties: it is acid stable and has 100% oral bioavailability; it also has excellent distribution properties, crosses the blood-brain barrier, and there is direct evidence of tumour localisation. This review seeks to unravel some of the mysteries of the imidazotetrazine class of compounds to which TMZ belongs. In addition to an overview of different synthetic strategies, we explore the somewhat unusual chemical reactivity of the imidazotetrazines, probing their mechanisms of reaction, examining which attributes are required for an active drug molecule and reviewing the use of this combined knowledge towards the development of new and improved anti-cancer agents. Full article
(This article belongs to the Special Issue Prodrugs: from Design to Clinic)
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