New bis(SATE) prodrug of AZT 5′‐monophosphate: In vitro anti‐HIV activity, stability, and potential oral absorption

Shafiee, Manijeh; Deferme, S.; Villard, Anne‐Laure; Egron, David; Gosselin, Gilles; Imbach, J.‐L.; Lioux, T.; Pompon, A.; Varray, S.; Aubertin, Anne-Marie; Mooter, Guy Van den; Kinget, Renaat; Philouze, Christian; Augustijns, Patrick

doi:10.1002/1520-6017(200104)90:4<448::aid-jps1003>3.0.co;2-h

Cited by 33 publications

(31 citation statements)

References 34 publications

(35 reference statements)

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“…-0.93 [26]) , log P 7eo = -2.3] than those for AZT [which is equally lipo-and hydrophilic; log P AZT = 0.06 (lit. -0.01 -0.1 [27][28][29]), log P 7ax = -0.7 --2.1] could be noted. However, similarly low log P's were found for phosphoramidates of much more lipophilic ABC [log P ABC = 1.16 (lit.…”

Section: Biological Evaluationmentioning

confidence: 99%

Aryl H-Phosphonates 18. Synthesis, properties, and biological activity of 2′,3′-dideoxynucleoside (N-heteroaryl)phosphoramidates of increased lipophilicity

Kolodziej

Romanowska

Stawiński

et al. 2015

European Journal of Medicinal Chemistry

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Section: Biological Evaluationmentioning

confidence: 99%

Aryl H-Phosphonates 18. Synthesis, properties, and biological activity of 2′,3′-dideoxynucleoside (N-heteroaryl)phosphoramidates of increased lipophilicity

Kolodziej

Romanowska

Stawiński

et al. 2015

European Journal of Medicinal Chemistry

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“…3). Our stability data on prodrug 2 is consistent with that reported for S-acyl-2-thioethyl pronucleotides (Shafiee et al, 2001). However, the mechanistic rationale for the greater stability of 2 in SGF compared with 1 is not established as yet.…”

Section: Downloaded Frommentioning

confidence: 99%

Metabolism, Pharmacokinetics, Tissue Distribution, and Stability Studies of the Prodrug Analog of an Anti-Hepatitis B Virus Dinucleoside Phosphorothioate

Coughlin¹,

Pandey²,

Padmanabhan³

et al. 2012

Drug Metab Dispos

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ABSTRACT:The alkoxycarbonyloxy dinucleotide prodrug R p , S p -2 is an orally bioavailable anti-hepatitis B virus agent. The compound is efficiently metabolized to the active dinucleoside phosphorothioate R p , S p -1 by human liver microsomes and S9 fraction without cytochrome P450-mediated oxidation or conjugation. The conversion of R p , S p -2 to R p , S p -1 appears to be mediated by liver esterases, occurs in a stereospecific manner, and is consistent with our earlier reported studies of serum-mediated hydrolytic conversion of R p , S p -2 to R p , S p -1. However, further metabolism of R p , S p -1 does not occur. The presence of a minor metabolite, the desulfurized product 10 was noted. The prodrug R p , S p -2 was quite stable in simulated gastric fluid, whereas the active R p , S p -1 had a half-life of <15 min. In simulated intestinal fluid, the prodrug 2 was fully converted to 1 in approximately 3 h, whereas 1 remained stable. To ascertain the tissue distribution of the prodrug 2 in rats, the synthesis of 35 S-labeled R p , S p -2 was undertaken. Tissue distribution studies of orally and intravenously administered radiolabeled [ 35 S]2 demonstrated that the radioactivity concentrates in the liver, with the highest liver/plasma ratio in the intravenous group at 1 h being 3.89 (females) and in the oral group at 1 h being 2.86 (males). The preferential distribution of the dinucleotide 1 and its prodrug 2 into liver may be attributed to the presence of nucleoside phosphorothioate backbone because phosphorothioate oligonucleotides also reveal a similar tissue distribution profile upon intravenous administration.

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“…Achiral chromatographic methods using C8 or C18 phase and polar organic eluent can be used for the resolution of diastereoisomers. Nevertheless, methods described in the literature for the separation of phosphotriesters and phosphoramidates containing a phosphorus asymmetric center [19,[22][23][24][25][26][27] lead to poor separative performances. As a result, development of chiral separation method was chosen.…”

Section: Introductionmentioning

confidence: 97%

“…Amoung chiral HPLC methods proposed for the separation of phosphotriesters and phosphoramidates diastereoisomers [30][31][32][33][34][35][36][37], few separations were carried out in reversed-phase mode using immobilised cyclodextrins [34] or polysaccharide type stationary phases [24][25][26][27][30][31][32][33][34][35][36]. Most proposed methods are based on the use of Pirkle [31][32][33] or polysaccharide type phases in normal-phase mode [23,34,37], which lead to efficient separation.…”

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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New bis(SATE) prodrug of AZT 5′‐monophosphate: In vitro anti‐HIV activity, stability, and potential oral absorption

Cited by 33 publications

References 34 publications

Aryl H-Phosphonates 18. Synthesis, properties, and biological activity of 2′,3′-dideoxynucleoside (N-heteroaryl)phosphoramidates of increased lipophilicity

Aryl H-Phosphonates 18. Synthesis, properties, and biological activity of 2′,3′-dideoxynucleoside (N-heteroaryl)phosphoramidates of increased lipophilicity

Metabolism, Pharmacokinetics, Tissue Distribution, and Stability Studies of the Prodrug Analog of an Anti-Hepatitis B Virus Dinucleoside Phosphorothioate

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

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