<i>O</i>-Alkoxyamidine Prodrugs of Furamidine:  In Vitro Transport and Microsomal Metabolism as Indicators of in Vivo Efficacy in a Mouse Model of <i>Trypanosoma brucei rhodesiense</i> Infection

Ansede, John H.; Anbazhagan, M.; Brun, Reto; Easterbrook, Judy; Hall, James Edwin; Boykin, David W.

doi:10.1021/jm030604o

Cited by 63 publications

(72 citation statements)

References 10 publications

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“…The amidoxime metabolites of DB844 and DB868 lost the oral activity of the prodrugs. Previously, diamidoxime prodrugs have been shown to be less potent in the STIB900 acute model in several but not all cases (2,16).…”

Section: Discussionmentioning

confidence: 99%

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New Treatment Option for Second-Stage African Sleeping Sickness: In Vitro and In Vivo Efficacy of Aza Analogs of DB289

Wenzler

Boykin

Ismail

et al. 2009

Antimicrob Agents Chemother

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112

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African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol-and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.

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Section: Discussionmentioning

confidence: 99%

“…Several of those analogs were effective in our stringent T. b. rhodesiense strain STIB900 acute mouse model (2). However, only a very few have shown good activity in the T. b. brucei strain GVR35 mouse CNS model.…”

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confidence: 96%

New Treatment Option for Second-Stage African Sleeping Sickness: In Vitro and In Vivo Efficacy of Aza Analogs of DB289

Wenzler

Boykin

Ismail

et al. 2009

Antimicrob Agents Chemother

Self Cite

112

159

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“…A single compound, DB289, is currently in phase III trials toward registration for use against early-stage HAT (Jannin and Cattand, 2004). DB289 is an orally available amidoxime prodrug (Zhou et al, 2002;Ansede et al, 2004) and is converted to the active diamidine, DB75, systemically (Sturk et al, 2004). Studies conducted in yeast cells (Lanteri et al, 2004) and in bloodstream forms of Trypanosoma brucei (C. Lanteri, unpublished data) suggest that the mitochondrion is a cellular target of DB75 action.…”

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confidence: 99%

Roles for theTrypanosoma bruceiP2 Transporter in DB75 Uptake and Resistance

et al. 2006

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A novel trypanocide, 2,5-bis(4-amidinophenyl)furan (DB75), in its prodrug amidoxime-derivative form, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289), is in trials as the first orally administered drug for human African trypanosomiasis. DB75 is a diamidine. Resistance to some diamidines correlates to loss of uptake via the P2 aminopurine transporter. We show here that uptake of DB75 into Trypanosoma brucei also occurs principally via the P2 transporter. Uptake of tritiated DB75 occurred via a high-affinity (K m app , 3.2 M) carriermediated route that was inhibited by adenosine, adenine, and pentamidine, all known substrates of the P2 transporter. Trypanosomes lacking the TbAT1 gene that encodes the P2 transporter demonstrated an 11-fold reduction in sensitivity to DB75 when measured under controlled in vitro conditions. These knockout cells were also less sensitive to DB75 than wild-type cells in mice. Initial uptake rates of DB75 into the ⌬tbat1 knockout cell line were greatly reduced compared with rates in wildtype cells. A trypanosome cell line selected in vitro for DB75 resistance was shown to have lost P2-mediated DB75 uptake. The TbAT1 gene was mapped to chromosome V of the T. brucei genome and the DB75-resistant parasites were shown to have deleted both alleles of this gene. Fluorescence microscopy of DB75-treated trypanosomes revealed that DB75 fluorescence localizes rapidly within the DNA-containing organelles of wild-type trypanosomes, whereas no fluorescence was observed in ⌬tbat1-null parasites or in the parasites selected for resistance to DB75.

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“…The latter is reduced to furamidine 29 in a cytochrome b 5 -mediated reaction (Fig. 12) [171]. DB289 30 has originally been developed for the treatment of the first stage of African sleeping sickness.…”

Section: Pafuramidine (Db289)mentioning

confidence: 99%

Antimalarial Drugs – What is in Use and What is in the Pipeline

Schlitzer¹

2008

Archiv der Pharmazie

131

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Malaria continues to be a potentially fatal threat to almost half of the world's population. In light of this threat, the armory to fight this disease is rather limited. Resistance against the most common and affordable antimalarials is widespread. Only few new drugs are in clinical development, most of them belong to long used classes of antimalarial drugs. This review will concisely cover the drugs which are currently in use, and describe the drug candidates which are in clinical evaluation.

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O-Alkoxyamidine Prodrugs of Furamidine: In Vitro Transport and Microsomal Metabolism as Indicators of in Vivo Efficacy in a Mouse Model of Trypanosoma brucei rhodesiense Infection

Cited by 63 publications

References 10 publications

New Treatment Option for Second-Stage African Sleeping Sickness: In Vitro and In Vivo Efficacy of Aza Analogs of DB289

New Treatment Option for Second-Stage African Sleeping Sickness: In Vitro and In Vivo Efficacy of Aza Analogs of DB289

Roles for theTrypanosoma bruceiP2 Transporter in DB75 Uptake and Resistance

Antimalarial Drugs – What is in Use and What is in the Pipeline

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