Phosphoramidate Derivatives of AZT as Inhibitors of HIV: Studies on the Carboxyl Terminus

McGuigan, Christopher; Pathirana, Ranjith; Choi, Sunhea; Kinchington, D.; O’Connor, Tim

doi:10.1177/095632029300400204

Cited by 19 publications

(14 citation statements)

References 14 publications

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“…The monoamidate prodrugs of the monophosphate of AZT exhibit minimal or no enhancement in in vitro anti-HIV activity (16,17). The modest in vitro effects seen with these AZT prodrugs have been explained in part by the lability of the AZT monophosphate bond, which can readily hydrolyze back to AZT.…”

Section: Discussionmentioning

confidence: 99%

Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus Reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue

Lee

Eisenberg

et al. 2005

Antimicrob Agents Chemother

311

293

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An isopropylalaninyl monoamidate phenyl monoester prodrug of tenofovir (GS 7340) was prepared, and its in vitro antiviral activity, metabolism, and pharmacokinetics in dogs were determined. The 50% effective concentration (EC 50 ) of GS 7340 against human immunodeficiency virus type 1 in MT-2 cells was 0.005 M compared to an EC 50 of 5 M for the parent drug, tenofovir. The (L)-alaninyl analog (GS 7340) was >1,000-fold more active than the (D)-alaninyl analog. GS 7340 has a half-life of 90 min in human plasma at 37°C and a half-life of 28.3 min in an MT-2 cell extract at 37°C. The antiviral activity (>10؋ the EC 50 ) and the metabolic stability in MT-2 cell extracts (>35؋) and plasma (>2.5؋) were also sensitive to the stereochemistry at the phosphorus. After a single oral dose of GS 7340 (10 mg-eq/kg tenofovir) to male beagle dogs, the plasma bioavailability of tenofovir compared to an intravenous dose of tenofovir was 17%. The total intracellular concentration of all tenofovir species in isolated peripheral blood mononuclear cells at 24 h was 63 g-eq/ml compared to 0.2 g-eq/ml in plasma. A radiolabeled distribution study with dogs resulted in an increased distribution of tenofovir to tissues of lymphatic origin compared to the commercially available prodrug tenofovir DF (Viread).Highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus is effective in reducing plasma viral loads below current assay detection limits and is responsible for significant reductions in AIDS-related mortality in the United States (13). Combinations of protease and reverse transcriptase inhibitors are extremely potent at blocking de novo infection; however, they have no effect on latently infected cells. The half-lives of these latent cellular reservoirs were originally estimated to be Ͼ3 years, leading to the conclusion that it may not be possible to eradicate human immunodeficiency virus (HIV) from an infected individual by using current HAART (2). It has subsequently been shown that even in patients who have undetectable plasma viremia (Ͻ50 copies/ ml), low-level replication is ongoing (11,15,36), resulting in repopulation of latent reservoirs and thus accounting for the long apparent half-lives observed (12,22,23,35). The failure of HAART to completely shut down virus replication in vivo is a function of both the intrinsic potency of the drug regimen and its distribution to the cellular sites of virus replication. The lymphatic tissues and the peripheral blood mononuclear cells (PBMCs) are the primary sites of virus replication and potential virus latency (9,19). A drug targeting strategy that selectively enhances active drug concentrations in these tissues without excessive systemic exposure is conceptually attractive and would potentially lead to a more effective HAART with fewer potential side effects.Tenofovir, {9-[(R)-2(phosphonomethoxy)propyl]adenine} (PMPA) (Fig.

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Section: Discussionmentioning

confidence: 99%

Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus Reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue

Lee

Eisenberg

et al. 2005

Antimicrob Agents Chemother

311

293

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“…Changes in the alaninyl carboxylate ester moiety of the trichloroethyl AZT-alaninyl phosphoramidate diester revealed that although increasing steric bulk of the ester group was associated with decreasing activity, changes in the ester did not signi®cantly affect the anti-HIV-1 activity in C8166. 131 Interestingly, p-bromo phenol alaninyl phosphoramidates of AZT have been shown to have potent spermicidal, as well as, anti-HIV-1 activity and may be useful as vaginal antiviral prophylactics. 146±149 Polyether para-substituted aryl phosphoramidates have also been constructed and shown to improve the water solubility of aryl amino acid phosphoramidates by 30-fold with little effect on antiviral potency.…”

Section: Phosphoramidate Diestersmentioning

confidence: 99%

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Wagner¹,

Iyer²,

McIntee³

2000

Med. Res. Rev.

264

215

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To overcome the many hurdles preventing the use of antiviral and anticancer nucleosides as therapeutics, the development of a prodrug methodology (i.e., pronucleotide) for the in vivo delivery of nucleotides has been proposed as a solution. The ideal pronucleotide should be non‐toxic, stable in plasma and blood, capable of being i.v. and/or orally dosed, and intracellularly convertible to the corresponding nucleotide. Although this goal has yet to be achieved, many clever and imaginative pronucleotide approaches have been developed, which are likely to be important pharmacological tools. This review will discuss the major advances and future directions of the emerging field of antiviral and anticancer pronucleotide design and development. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 6, 417–451, 2000

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“…The generality of the MMPA platform to other phenolic drugs with more complicated structures was investigated. Phosphonamidate prodrugs of phenolic drugs SN38 24 (14), estradiol 25 (16), and naloxone 26 (18) (Figure 4) were synthesized by using the same method as described for compounds 3−9 (Scheme 1). The pharmacokinetic profiles of compounds 15, 17, and 19, each as a mixture of its diastereoisomeric pair, were evaluated in beagle dogs via oral administration (Table 4).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Previous attempts to make 1 orally bioavailable through formulation and prodrug modifications have met with limited success. − Our efforts turned to the aryloxyphosphonamidate ProTide technology first reported by the McGuigan group, − which was used subsequently by Gilead Sciences for the marketed drug tenofovir alafenamide . As illustrated with the prodrug of tenofovir ( A , Figure ), oral absorption is facilitated by the neutral phosphonamidate A of tenofovir with an amino acid ester and phenol.…”

Section: Introductionmentioning

confidence: 99%

Oral Delivery of Propofol with Methoxymethylphosphonic Acid as the Delivery Vehicle

Wei¹,

Qiu²,

Lei³

et al. 2017

J. Med. Chem.

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Phosphonamidate 3a of methoxymethylphosphonic acid (MMPA) with propofol (1) and l-alanine ethyl ester was found to be an efficient scaffold for the oral delivery of compound 1. The synthesis and evaluation of MMPA based phosphonamidates of compound 1, HSK3486 (2), and other phenolic drugs revealed the general application of MMPA as the effective delivery vehicle for phenolic drugs. On the basis of plasma concentrations of compound 1 and SN38 (14), the oral bioavailability of compound 3a and 15 in beagle dogs was found to be 97.6% and 34.1%, respectively.

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Phosphoramidate Derivatives of AZT as Inhibitors of HIV: Studies on the Carboxyl Terminus

Cited by 19 publications

References 14 publications

Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus Reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue

Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus Reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Oral Delivery of Propofol with Methoxymethylphosphonic Acid as the Delivery Vehicle

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