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Topical Collection "Prodrugs: from Design to Clinic"

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A topical collection in Pharmaceuticals (ISSN 1424-8247).

Editors

Guest Editor
Prof. Dr. Jarkko Rautio (Website)

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
Co-Guest Editor
Dr. Kristiina Huttunen

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O.Box 1627, FI-70211 Kuopio, Finland
Interests: design and discovery of prodrugs; perforin inhibitors

Topical Collection Information

Dear Colleagues,

We would like to invite you to submit an original manuscript, communication or review for this collection. 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
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Papers will be published continuously (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Keywords

  • prodrugs
  • bioprecursor
  • bioconversion

Related Special Issues

Published Papers (7 papers)

2014

Open AccessReview The Medicinal Chemistry of Imidazotetrazine Prodrugs
Pharmaceuticals 2014, 7(7), 797-838; doi:10.3390/ph7070797
Received: 3 April 2014 / Revised: 17 June 2014 / Accepted: 18 June 2014 / Published: 10 July 2014
Cited by 4 | PDF Full-text (2242 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessArticle Conformational Analysis, Molecular Structure and Solid State Simulation of the Antiviral Drug Acyclovir (Zovirax) Using Density Functional Theory Methods
Pharmaceuticals 2014, 7(6), 695-722; doi:10.3390/ph7060695
Received: 16 January 2014 / Revised: 22 May 2014 / Accepted: 26 May 2014 / Published: 6 June 2014
Cited by 3 | PDF Full-text (1903 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] 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
Open AccessArticle Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug
Pharmaceuticals 2014, 7(6), 676-694; doi:10.3390/ph7060676
Received: 13 March 2014 / Revised: 15 May 2014 / Accepted: 19 May 2014 / Published: 28 May 2014
PDF Full-text (592 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] 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
Figures

Open AccessArticle Synthesis, Screening and Pharmacokinetic Evaluation of Potential Prodrugs of Bupropion. Part One: In Vitro Development
Pharmaceuticals 2014, 7(5), 595-620; doi:10.3390/ph7050595
Received: 13 March 2014 / Revised: 30 April 2014 / Accepted: 8 May 2014 / Published: 14 May 2014
PDF Full-text (653 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] 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
Figures

Open AccessArticle Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir
Pharmaceuticals 2014, 7(4), 433-452; doi:10.3390/ph7040433
Received: 23 January 2014 / Revised: 24 March 2014 / Accepted: 31 March 2014 / Published: 10 April 2014
Cited by 6 | PDF Full-text (419 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] 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
Figures

Open AccessArticle Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization
Pharmaceuticals 2014, 7(2), 207-219; doi:10.3390/ph7020207
Received: 20 January 2014 / Revised: 8 February 2014 / Accepted: 12 February 2014 / Published: 24 February 2014
Cited by 4 | PDF Full-text (128 KB) | HTML Full-text | XML Full-text
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 [...] 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
Open AccessArticle The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs
Pharmaceuticals 2014, 7(2), 169-191; doi:10.3390/ph7020169
Received: 26 November 2013 / Revised: 15 January 2014 / Accepted: 22 January 2014 / Published: 27 January 2014
Cited by 5 | PDF Full-text (514 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] 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

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