Practical Synthesis, Separation, and Stereochemical Assignment of the Pmpa Pro-Drug Gs-7340

Chapman, Harlan H.; Kernan, Michael R.; Prisbe, Ernest J.; Rohloff, John C.; Sparacino, Mark L.; Terhorst, Terry; Yu, Richard H.

doi:10.1081/ncn-100002338

Cited by 63 publications

(48 citation statements)

References 9 publications

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“…All compounds were provided by Gilead Sciences, Foster City, Calif., through the Antiviral Substances Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health (Bethesda, Md.). They were prepared by procedures described elsewhere (2,11,12,24,30). N 6 -substituted PMEDAPs were prepared according to the method of Holý et al (22).…”

Section: Methodsmentioning

confidence: 99%

“…Neutralization of the negative charges on the phosphonyl function in ANPs by substitution with a lipophilic group(s) generally enhances ANP permeation through cellular membrane and oral bioavailability. For this purpose, the alkyloxycarbonylphenyl prodrugs of cHPMPC (30), lipophilic alkoxyalkyl esters of cHPMPC (6,24), and bis(amidate) and aryl ester amidate prodrugs of ANPs (2,11,25) were investigated. In the latter two groups, phosphonamidates derived from alkyl L-alanine exhibit potent ac-tivities.…”

mentioning

confidence: 99%

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Evaluation of Nucleoside Phosphonates and Their Analogs and Prodrugs for Inhibition of Orthopoxvirus Replication

Keith

Hitchcock

Lee

et al. 2003

Antimicrob Agents Chemother

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In the event of a bioterrorism attack using smallpox virus, there currently is no approved drug for the treatment of infections with this virus. We have reported previously that (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC) (also known as cidofovir [CDV]) has good activity against poxvirus infections; however, a major limitation is the requirement for intravenous administration. Two related acyclic nucleoside phosphonates (ANPs), adefovir (PMEA) and tenofovir (PMPA), are active against human immunodeficiency virus or hepatitis B virus but do not have activity against the orthopoxviruses. Therefore, we have evaluated a number of analogs and potential oral prodrugs of these three compounds for their ability to inhibit the replication of vaccinia virus or cowpox virus in tissue culture cells. The most-active compounds within the CDV series were (S)-HPMPA and (butyl L-alaninyl) cyclic HPMPC, with 50% effective concentrations (EC 50 s) from 4 to 8 M, compared with 33 to 43 M for CDV. Although PMEA itself was not active, adefovir dipivoxil {bis[(pivaloyl)oxymethyl] PMEA} and bis(butyl L-alaninyl) PMEA were active against both viruses, and bis (butyl L-alaninyl) PME-N6-(cyclopropyl)DAP and (isopropyl L-alaninyl)phenyl PME-N6-(cyclopropyl)DAP were the most active compounds tested, with EC 50 s of 0.1 to 2.6 M. In the PMPA series, none of the analogs tested had significantly better activity than PMPA itself. These data indicate that a number of these ANP derivatives have activity against vaccinia virus and cowpox virus in vitro and should be evaluated for their efficacies in animal models.The success of the acyclic nucleoside phosphonate analogs (ANPs) as broad-spectrum antiviral agents with potent and selective activity in vitro and in vivo is the result of selective interactions of their diphosphate metabolite, which acts as both a competitive inhibitor and an alternative substrate with the viral DNA polymerase. The prototype compounds for this class of agents are (S)-1-[3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (HPMPC) (also known as cidofovir [CDV]), 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) (also known as adefovir), and (R)-9-[2-(phosphonomethoxy) propyl]adenine (PMPA) (also known as tenofovir). CDV, which is the best-known member of this class of compounds, and its cyclic ester cHPMPC have potent and prolonged in vitro and in vivo activity against several herpesviruses, including herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus (16,17,28). CDV is currently approved for treatment of cytomegalovirus retinitis in patients with AIDS (26, 32). In addition, CDV is a potent inhibitor of poxvirus replication in vitro (24,25,35) and has been shown to be very effective against both vaccinia virus (VV) and cowpox virus (CV) infections in animal models

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Evaluation of Nucleoside Phosphonates and Their Analogs and Prodrugs for Inhibition of Orthopoxvirus Replication

Keith

Hitchcock

Lee

et al. 2003

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…[103] Next, the Gilead group developed a practical large-scale synthesis of GS-7340 (41), which also A C H T U N G T R E N N U N G allowed separation of the distereoisomers. [104] Interestingly, the group chose the S-isomer for development as an HIV inhibitor because it was found to be~10-fold more potent than the Risomer. [104] However, Gilead recently discontinued the development of GS-7340 (41) as they did not believe that GS-7340 (41) has a profile that differentiates it to an extent that supports its continued development.…”

Section: Gs-7340 and Gs-9131mentioning

confidence: 99%

“…[104] Interestingly, the group chose the S-isomer for development as an HIV inhibitor because it was found to be~10-fold more potent than the Risomer. [104] However, Gilead recently discontinued the development of GS-7340 (41) as they did not believe that GS-7340 (41) has a profile that differentiates it to an extent that supports its continued development.…”

Section: Gs-7340 and Gs-9131mentioning

confidence: 99%

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

2009

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Prodrug technologies aimed at delivering nucleoside monophosphates into cells (protides) have proved to be effective in improving the therapeutic potential of antiviral and anticancer nucleosides. In these cases, the nucleoside monophosphates are delivered into the cell, where they may then be further converted (phosphorylated) to their active species. Herein, we describe one of these technologies developed in our laboratories, known as the phosphoramidate protide method. In this approach, the charges of the phosphate group are fully masked to provide efficient passive cell-membrane penetration. Upon entering the cell, the masking groups are enzymatically cleaved to release the phosphorylated biomolecule. The application of this technology to various therapeutic nucleosides has resulted in improved antiviral and anticancer activities, and in some cases it has transformed inactive nucleosides to active ones. Additionally, the phosphoramidate technology has also been applied to numerous antiviral nucleoside phosphonates, and has resulted in at least three phosphoramidate-based nucleotides progressing to clinical investigations. Furthermore, the phosphoramidate technology has been recently applied to sugars (mainly glucosamine) in order to improve their therapeutic potential. The development of the phosphoramidate technology, mechanism of action and the application of the technology to various monophosphorylated nucleosides and sugars will be reviewed.

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“…1). Due to the asymmetric center at phosphorous and the non-stereoselective synthetic route [6], GS-7171 was composed of a 1:1 mixture of two diastereomers (GS-7339 and GS-7340); the (R)-PMPA side-chain and l-amino acid ester were homochiral starting materials. The high oral bioavailability and favorable tissue-selective distribution of GS-7340 made it a promising candidate for HBV therapy [7].…”

Section: Introductionmentioning

confidence: 99%

A Rapid and Sensitive LC Method for Determination of Diastereomeric Purity of Tenofovir Alafenamide

Wang

et al. 2014

Chromatographia

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Practical Synthesis, Separation, and Stereochemical Assignment of the Pmpa Pro-Drug Gs-7340

Cited by 63 publications

References 9 publications

Evaluation of Nucleoside Phosphonates and Their Analogs and Prodrugs for Inhibition of Orthopoxvirus Replication

Evaluation of Nucleoside Phosphonates and Their Analogs and Prodrugs for Inhibition of Orthopoxvirus Replication

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

A Rapid and Sensitive LC Method for Determination of Diastereomeric Purity of Tenofovir Alafenamide

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