<i>S</i>-Acyl-2-thioethyl Phosphoramidate Diester Derivatives as Mononucleotide Prodrugs

Egron, David; Imbach, Jean‐Louis; Gosselin, Gilles; Aubertin, ‡ and Anne-Marie; Philouze, Christian

doi:10.1021/jm0308444

Cited by 36 publications

(31 citation statements)

References 45 publications

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“…However, PQD was the only metabolite measurable in all samples at any time point; the monoethylcarbamyl PQD was not detected. PQD-BE appears to be a one-step hydrolysis derivative (1,9). Unlike PQD-A4, which was undetectable in blood, PQD-BE was demonstrable in most of the blood samples, with a mean elimination half-life of 9.3 Ϯ 5.1 h. This suggests that PQD-BE was directly hydrolyzed to PQD without any steps in between.…”

Section: Discussionmentioning

confidence: 91%

Pharmacokinetics, Safety, and Hydrolysis of Oral Pyrroloquinazolinediamines Administered in Single and Multiple Doses in Rats

Kozar

Shearer

et al. 2007

Antimicrob Agents Chemother

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Pyrroloquinazolinediamine (PQD) derivatives such as tetra-acetamide PQD (PQD-A4) and bis-ethylcarbamyl PQD (PQD-BE) were much safer (with therapeutic indices of 80 and 32, respectively) than their parent compound, PQD (therapeutic index, 10). Further evaluation of PQD-A4 and PQD-BE in single and multiple pharmacokinetic (PK) studies as well as corresponding toxicity studies was conducted with rats. PQD-A4 could be converted to two intermediate metabolites (monoacetamide PQD and bisacetamide PQD) first and then to the final metabolite, PQD, while PQD-BE was directly hydrolyzed to PQD without precursor and intermediate metabolites. Maximum tolerant doses showed that PQD-A4 and PQD-BE have only 1/12 and 1/6, respectively, of the toxicity of PQD after a single oral dose. Compared to the area under the concentration-time curve for PQD alone (2,965 ng ⅐ h/ml), values measured in animals treated with PQD-A4 and PQD-BE were one-third (1,047 ng ⅐ h/ml) and one-half (1,381 ng ⅐ h/ml) as high, respectively, after an equimolar dosage, suggesting that PQD was the only agent to induce the toxicity. Similar results were also shown in multiple treatments; PQD-A4 and PQD-BE generated two-fifths and three-fifths, respectively, of PQD concentrations, with 8.8-fold and 3.8-fold safety margins, respectively, over the parent drug. PK data indicated that the bioavailability of oral PQD-A4 was greatly limited at high dose levels, that PQD-A4 was slowly converted to PQD via a sequential three-step process of conversion, and that PQD-A4 was significantly less toxic than the one-step hydrolysis drug, PQD-BE. It was concluded that the slow and smaller release of PQD was the main reason for the reduction in toxicity and that the active intermediate metabolites can still maintain antimalarial potency. Therefore, the candidate with multiple-step hydrolysis of PQD could be developed as a safer potential agent for malaria treatment.Pyrroloquinazolinediamine {PQD; 7-(substituted)-7H-pyrrolo[3,2-f] quinazoline-1,3-diamines} has been reported to possess anticancer, antimicrobial, and antimalarial activities (15). PQD was reported to be a very active antimalarial agent both in vivo and in vitro (7,10,15). The compounds were potent inhibitors of fungal and human dihydrofolate reductase and were highly active against Candida albicans and an array of tumor cell lines (8, 12). The compounds were active in lung and brain tumor models and displayed in vivo activity against Pneumocystis carinii and C. albicans (8,24). PQD acted as an inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and could rapidly and very selectively shut down epidermal growth factor-stimulated signal transmission by binding competitively at the ATP site of the EGFR (2). Another new oral PQD derivative exerts analgesic and antiinflammatory effects, which were related to dual inhibition of cyclo-oxygenase-2 and 5-lipoxygenase activities (13,21).PQD was reported to be very active as an antimalarial agent both in vivo and in vitro. However, this com...

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Section: Discussionmentioning

confidence: 91%

Pharmacokinetics, Safety, and Hydrolysis of Oral Pyrroloquinazolinediamines Administered in Single and Multiple Doses in Rats

Kozar

Shearer

et al. 2007

Antimicrob Agents Chemother

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“…1) were synthesized, as diastereoisomeric mixtures, following adapted procedures [11,12,15] leading to mixture of two diastereoisomers.…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…To improve the oral bioavailability of these potential therapeutic agents, i.e. their intestinal absorption, a new series of compounds incorporating an amino acid residue was synthesized [10][11][12][13][14][15]. Permeation of these phosphoramidates across the intestinal mucosa could namely be increased by active transport [16].…”

Section: Introductionmentioning

confidence: 99%

Separation of nucleoside phosphoramidate diastereoisomers by high performance liquid chromatography and capillary electrophoresis☆

Goossens

Roux

Egron

et al. 2008

Journal of Chromatography B

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“…A large number of t-BuSATE phosphoramidate diesters of AZT (Fig. 8) bearing various methyl-esterified amino acids, as well as aliphatic and aromatic amino residues have been synthesised and studied [40,41].…”

Section: Mononucleoside Sate Phosphoramidate Diestersmentioning

confidence: 99%

Biolabile constructs for pronucleotide design

Jochum

Schlienger

Egron

et al. 2005

Journal of Organometallic Chemistry

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S-Acyl-2-thioethyl Phosphoramidate Diester Derivatives as Mononucleotide Prodrugs

Cited by 36 publications

References 45 publications

Pharmacokinetics, Safety, and Hydrolysis of Oral Pyrroloquinazolinediamines Administered in Single and Multiple Doses in Rats

Pharmacokinetics, Safety, and Hydrolysis of Oral Pyrroloquinazolinediamines Administered in Single and Multiple Doses in Rats

Separation of nucleoside phosphoramidate diastereoisomers by high performance liquid chromatography and capillary electrophoresis☆

Biolabile constructs for pronucleotide design

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