Phosphoramidate prodrugs

A direct reaction of activation is exemplified by the NK receptor antagonist L-754,030 (9.78) developed as an i.v. drug against emesis, migraine, and chronic pain. Because the compound has a low water solubility unfavorable for i.v. administration, a phosphoramidate prodrug (9.77) has been examined [152], This compound hydrolyzed rapidly under acidic conditions. More importantly, it was rapidly converted to L-754,030 in rat blood but was... 

S. W. Huskey, D. Luffer-Atals, B. J. Dean, E. M. McGowan, W. P. Feeney, S. H. Lee Chiu, Substance P Receptor Antagonist I Conversion of Phosphoramidate Prodrug after i.v. Administration to Rats and Dogs , Drug Metab. Dispos. 1999, 27, 1367- 1373. 

The novel 5-fluoro-2 -deoxyuridine phosphoramidate prodrug 195 has been prepared, along with the compound with only one bromoethyl group. The... 

Vemachio JH, Bleiman B, Bryant KD, Chamberlain S, Hunley D, Hutchins J, Ames B, Gorovits E, Ganguly B, Hall A et al (2011) INX-08189, a phosphoramidate prodrug of 6-0-melhyl-2 -C-methyl guanosine, is a potent inhibitor of hepatitis C virus replication with excellent pharmacokinetic and pharmacodynamic properties. Antimicrob Agents Chemother 55 1843-1851... 

Tobias SC, Borch RF (2001) Synthesis and biological studies of novel nucleoside phosphoramidate prodrugs. J Med Chem 44 4475-4480... 

Tobias SC, Borch RF (2004) Synthesis and biological evaluation of a cytarabine phosphoramidate prodrug. Mol Pharm 1 112-116... 

Gardelli C, Attenni B, Donghi M, Meppen M, Pacini B, Harper S, Di Marco A, Fiore F, Giuliano C, Pucci V et al (2009) Phosphoramidate prodrugs of 2 -C-methylcytidine for therapy of hepatitis C virus infection. J Med Chem 52 5394—5407... 

Arbelo Roman C, Balzarini J, Meier C (2010) Diastereoselective s)mthesis of aryloxy phosphoramidate prodrugs of 3 -deoxy-2 ,3 -didehydrothymidine monophosphate. J Med Chem 53 7675-7681... 

The SAR study on phosphoramidate prodrugs of PSI-6206 was focused on the aryloxy-phosphoramidate side chain. Compared to the common aryloxy-phosphoramidate prodrugs, modifications at amino acid ester, aryl phosphate ester, and amino acid side chain were conducted on PSI-6206 phosphoramidate. An examination of these modifications for 29 compounds found that a small simple alkyl and branched alkyl at the amino acid ester, phenyl and halogenated aryl at the phosphate ester, and a-methyl at the amino acid side chain produced better antiviral activity and the least cytotoxicity. The groups for the amino acid ester part (R ) were chosen from methyl, ethyl, isopropyl, and cyclohexyl the groups for the aryl phosphate ester (R ) were selected from phenyl and para-halogenated phenyl and the substituent for the amino acid side chain was fixed with a-methyl (r-alanine). These combinations of modifications resulted in 16 compounds (12-27, Table 1) for further evaluation. 

Table 1. HCV replicon activity of 16 phosphoramidate prodrugs with simultaneous carboxylate and phosphate ester modification.

Table 2. PK parameters of 2 -deoxy-2 -fluoro-2 -C-methyluridine triphosphate (11) in rat liver after an oral dose of 50 mg/kg for seven phosphoramidate prodrugs.

A novel approach for the intra-cellular delivery of aryl phosphate peptidomi-metics has been developed. This approach consists of cell membrane permeable phosphoramide prodrugs (e.g., (48)) that undergo intracellular enzymatic activation followed by intramolecular cyclization and hydrolysis to generate the phosphate dianions (Scheme 8). ... 

Shi J, McBrayer TR, Whitaker T, Coats SJ, Zhou L, Zhang H, Detorio MA, Johns M, Bassit L, Schinazi RF, Powdrill MH, Goette M (2011) Synthesis and antiviral activity of 2 -deoxy-2 -fluoro-2 -C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5 -tri-phosphates. Bioorg Med Chem Lett 21 7094-7098... 

Here we illustrate our efforts towards the optimization of 2 -methyl-cytidine prodrugs employing a kinase-bypass approach based on 5 -phosphoramidate prodrugs (McGuigan). 

We will describe a novel class of phosphoramidate prodrugs based on aminoalcohols, the synthetic approach, the SAR and the in vivo and in vitro studies. 

Phosphoramidate prodrugs bearing an amino acid ester residue In one of the most widely-used pro-nucleotide strategies a nucleoside monophosphate is masked as a phosphoramidate or phosphordiamidate. Westwell, McGuigan and co-workers prepared a series of such derivatives 43 of an interesting fluorinated nucleoside, namely S -deojy-S -fluorothymidine. ... 

Researchers from Gilead Sciences prepared phosphoramidate prodrugs 46 of a C-nucleoside bearing 4-aza-7,9-dideaza adenine as a... 

Nucleoside phosphoramidates are the oxidised form of nucleoside phosphoramidites, but they are designed for different purposes. Nucleoside phosphoramidites are very reactive and used as the monomers for chemical synthesis of oligomers while nucleoside phosphoramidates are relatively stable and used primarily as prodrugs since the amidate moiety is often constructed by linking with a natural amino acid to enhance the cellular uptake of a phosphoramidate which is then hydrolysed to generate the desired nucleoside monophosphate. Cho et al. developed an efficient method for the synthesis of exo-N-carbamoyl nucleosides and their phosphoramidate prodrugs (51) in excellent yields. 

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