Synthesis, transport and antiviral activity of Ala–Ser and Val–Ser prodrugs of cidofovir

Peterson, Larryn W.; Kim, Jae‐Seung; Kijek, Paul; Mitchell, Stefanie; Hilfinger, John M.; Breitenbach, Julie M.; Borysko, Kathy; Drach, John C.; Kashemirov, B. A.; McKenna, Charles E.

doi:10.1016/j.bmcl.2011.04.126

Cited by 15 publications

(19 citation statements)

References 31 publications

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“…Despite an enhanced bioavailability, the dipetide (S)-cHPMPC conjugates having the second phosphonic OH masked with an ethyl group (47 and This enhanced oral bioavailability was tentatively justified by the authors as the results of a higher chemical and enzymatic stability compared to its cyclic analogue [79].…”

Section: Peptidomimetic Prodrugsmentioning

confidence: 99%

Medicinal Chemistry of Nucleoside Phosphonate Prodrugs for Antiviral Therapy

Pertusati

Serpi

McGuigan

2012

Antivir Chem Chemother

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Considerable attention has been focused on the development of phosphonate-containing drugs for application in many therapeutic areas. However, phosphonate diacids are deprotonated at physiological pH and thus phosphonate-containing drugs are not ideal for oral administration, an extremely desirable requisite for the treatment of chronic diseases. To overcome this limitation several prodrug structures of biologically active phosphonate analogues have been developed. The rationale behind the design of such agents is to achieve temporary blockade of the free phosphonic functional group until their systemic absorption and delivery, allowing the release of the active drug only once at the target. In this paper, an overview of acyclic and cyclic nucleoside phosphonate prodrugs, designed as antiviral agents, is presented.

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Section: Peptidomimetic Prodrugsmentioning

confidence: 99%

Medicinal Chemistry of Nucleoside Phosphonate Prodrugs for Antiviral Therapy

Pertusati

Serpi

McGuigan

2012

Antivir Chem Chemother

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“…57 Furthermore, the ( S )-HPMPC prodrugs incorporating dipeptide promoieties demonstrated an 8−15-fold increase in the oral bioavailability of total cidofovir species compared to the parent drug in a rodent in situ perfusion model. 58, 60 …”

Section: Dipeptide (S)-hpmpc Prodrugsmentioning

confidence: 99%

“…Similarly to the parent drug 1 , dipeptide prodrugs 7−12 were found to be up to 10-fold more potent in vitro against HCMV (IC 50 = 0.2−0.7 µM) compared to ganciclovir, the positive control (IC 50 = 3 µM), 55,58,60 but in contrast, they did not show any activity against orthopox viruses (vaccinia and cowpox viruses, IC 50 > 100 µM), despite the prodrugs’ improved metabolic stability and increased cell membrane permeability. The difference in potency against various viruses was attributed to the prodrugs’ inadequate activation in the viral assays caused by either lack of specific viral-encoded enzymes that activate the prodrugs or different assay incubation times (HCMV, 10 d; cowpox and vaccinia virus, 3 d).…”

Section: Dipeptide (S)-hpmpc Prodrugsmentioning

confidence: 99%

Evolution of an Amino Acid Based Prodrug Approach: Stay Tuned

et al. 2013

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Certain acyclic nucleoside phosphonates (ANPs) such as (S)-HPMPC (cidofovir, Vistide®) and (S)-HPMPA have been shown to be active against a broad spectrum of DNA and retroviruses. However, their poor absorption as well as their toxicity limit the utilization of these therapeutics in the clinic. Nucleoside phosphonates are poorly absorbed primarily due to the presence of the phosphonic acid group, which ionizes at physiological pH. When dosed intravenously they display dose-limiting nephrotoxicity due to their accumulation in the kidney. To overcome these limitations, nucleoside phosphonate prodrug strategies have taken center stage in the development pathway and a number of different approaches are at various stages of development. Our efforts have focused on the development of ANP prodrugs in which a benign amino acid promoiety masks a phosphonate P-OH via a hydroxyl side chain. The design of these prodrugs incorporates multiple chemical groups (the P−X−C linkage, the amino acid stereochemistry, the C-terminal and N-terminal functional groups) that can be been tuned to modify absorption, pharmacokinetic and efficacy properties with the goal of improving overall prodrug performance.

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“…In a recent study, HDP-CDV treatment of congenital infection increased pup survival but did not eliminate congenital infection [53]. A group of serine peptide phosphoester prodrugs of cCDV have also been investigated which have better bioavailabilty and activity to HCMV (and poxviruses) with reduced cytotoxicity and improved activity in the rat [57-59]. Overall these recent advances are potentially encouraging for the future development of CDV derivatives.…”

Section: CMV Antivirals and Viral Targetsmentioning

confidence: 99%

Cytomegalovirus antivirals and development of improved animal models

McGregor

Choi

2011

Expert Opinion on Drug Metabolism & Toxicology

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Introduction Cytomegalovirus (CMV) is a ubiquitous pathogen that establishes a life long asymptomatic infection in healthy individuals. Infection of immunesuppressed individuals causes serious illness. Transplant and AIDS patients are highly susceptible to CMV leading to life threatening end organ disease. Another vulnerable population is the developing fetus in utero, where congenital infection can result in surviving newborns with long term developmental problems. There is no vaccine licensed for CMV and current antivirals suffer from complications associated with prolonged treatment. These include drug toxicity and emergence of resistant strains. There is an obvious need for new antivirals. Candidate intervention strategies are tested in controlled pre-clinical animal models but species specificity of HCMV precludes the direct study of the virus in an animal model. Areas covered This review explores the current status of CMV antivirals and development of new drugs. This includes the use of animal models and the development of new improved models such as humanized animal CMV and bioluminescent imaging of virus in animals in real time. Expert Opinion Various new CMV antivirals are in development, some with greater spectrum of activity against other viruses. Although the greatest need is in the setting of transplant patients there remains an unmet need for a safe antiviral strategy against congenital CMV. This is especially important since an effective CMV vaccine remains an elusive goal. In this capacity greater emphasis should be placed on suitable pre-clinical animal models and greater collaboration between industry and academia.

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Synthesis, transport and antiviral activity of Ala–Ser and Val–Ser prodrugs of cidofovir

Cited by 15 publications

References 31 publications

Medicinal Chemistry of Nucleoside Phosphonate Prodrugs for Antiviral Therapy

Medicinal Chemistry of Nucleoside Phosphonate Prodrugs for Antiviral Therapy

Evolution of an Amino Acid Based Prodrug Approach: Stay Tuned

Cytomegalovirus antivirals and development of improved animal models

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