New Prodrugs of the Antiprotozoal Drug Pentamidine
Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76-78, 24118 Kiel, Germany. ChemMedChem
(Impact Factor: 2.97).
12/2011; 6(12):2233-42. DOI: 10.1002/cmdc.201100422
Pentamidine is an effective antimicrobial agent that is approved for the treatment of African trypanosomiasis but suffers from poor oral bioavailability and central nervous system (CNS) penetration. This work deals with the development and systematic characterisation of new prodrugs of pentamidine. For this reason, numerous prodrugs that use different prodrug principles were synthesised and examined in vitro and in vivo. Another objective of the study was the determination of permeability of the different pentamidine prodrugs. While some of the prodrug principles applied in this study are known, such as the conversion of the amidine functions into amidoximes or the O-alkylation of amidoximes with a carboxymethyl residue, others were developed more recently and are described here for the first time. These newly developed methods aim to increase the affinity of the prodrug for the transporters and mediate an active uptake via carrier systems by conjugation of amidoximes with compounds that improve the overall solubility of the prodrug. The different principles chosen resulted in several pentamidine prodrugs with various advantages. The objective of this investigation was the systematic characterisation and evaluation of eight pentamidine prodrugs in order to identify the most appropriate strategy to improve the properties of the parent drug. For this reason, all prodrugs were examined with respect to their solubility, stability, enzymatic activation, distribution, CNS delivery, and oral bioavailability. The results of this work have allowed reliable conclusions to be drawn regarding the best prodrug principle for the antiprotozoal drug pentamidine.
Figures in this publication
Available from: Andrew Hemphill
- "furamidine, DB820 and DB829, Figs 1 and 3) replacing the alkyl chain in the pentamidine. As discussed in the section 'Design and synthesis', various pro-drugs of diamidines have been designed to improve oral bioavailability, by masking the positive charge of the amidine moiety using hydroxy, alkyloxy, acetoxy and amino acids (Clement and Raether, 1985; Boykin et al. 1996; Ismail et al. 2003; Kotthaus et al. 2011). Biotransformation of pafuramidine (Fig. 3), the methoxy pro-drug of furamidine, to the active furamidine is complex, involving multiple steps of sequential oxidative O-demethylation and reductive N-dehydroxylation reactions that are catalysed by cytochrome P450 enzymes and the cytochrome b5/NADH b5 reductase system, respectively (Saulter et al. 2005; Wang et al. 2006, 2007). "
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ABSTRACT: SUMMARY Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.
Parasitology 04/2013; 140(8):1-23. DOI:10.1017/S0031182013000292 · 2.56 Impact Factor
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ABSTRACT: New 3-amidinophenylalanine-derived matriptase inhibitors were developed and tested against the related trypsin-like serine proteases matriptase-2, thrombin and factor Xa. The strongest matriptase inhibition was found for compounds containing an N-terminal 2′,4′-dichloro- or 2′,4′-dimethoxy-biphenyl-3-sulfonyl group. The combination with a C-terminal piperidyl-cyclohexylurea residue provided the first monobasic matriptase inhibitor with a Ki value < 3 nM and excellent selectivity over thrombin. The X-ray structure of a representative analogue in complex with thrombin superimposed with matriptase provides information regarding the selectivity profile observed in this study.
Medicinal Chemistry Communication 07/2012; 3(7):807-813. DOI:10.1039/C2MD20074K · 2.50 Impact Factor
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Predicting the pharmacokinetics (PK) of prodrugs and their corresponding active drugs is challenging, as there are many variables to consider. Prodrug conversion characteristics in different tissues are generally measured, but integrating these variables to a PK profile is not a common practice. In this paper, a joined in vitro/in silico-in vivo extrapolation (IVIVE) and physiologically-based pharmacokinetic (PBPK) modeling approach is presented to predict active drug exposure in human after oral prodrug administration.
Physico-chemical and in vitro assays as well as in silico predictions were proposed to characterize key pharmacokinetic properties (e.g. clearance, volume of distribution, conversion rates) of three marketed prodrugs. These data were used to parameterize a PBPK model for simulating human PK profiles of the active drugs after prodrug administration, which were compared to literature data by evaluating the accuracy and uncertainty of the predictions.
For mycophenate mofetil and midodrine the PK of their active moieties could be adequately predicted. The assumptions of the PBPK-IVIVE approach were valid, i.e. being hepatically cleared, converted in the gut lumen, blood and liver and not metabolized in the gut wall. However, the observed profiles after oral bambuterol administration clearly fell outside the prediction interval as the PBPK model failed to predict the observed bioavailability.
Adding quantitative information about prodrug conversion in the gut, liver and blood to a PBPK model for the absorption, distribution, metabolism and excretion (ADME) properties of prodrugs and their active moieties resulted, retrospectively, in reasonable predictions of the human PK when the ADME properties are well understood. Also in a prospective compound selection process, this integrative approach can improve decision making on prodrug candidates by putting relative differences in prodrug conversion of a large number of candidates into the perspective of their human PK profile, before conducting any in vivo experiments.
Journal of pharmacological and toxicological methods 12/2012; 67(3). DOI:10.1016/j.vascn.2012.12.002 · 2.39 Impact Factor
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