6‐[2‐(Phosphonomethoxy)alkoxy]‐2,4‐diaminopyrimidines: A New Class of Acyclic Pyrimidine Nucleoside Phosphonates with Antiviral Activity

Balzarini, Jan; Pannecouque, Christophe; Naesens, Lieve; Andrei, Gracíela; Snoeck, R.; Clercq, E. De; Hocková, Dana; Holý, Antonı́n

doi:10.1002/chin.200510222

Cited by 3 publications

(3 citation statements)

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“…Here, PMEO-DAPy emerged as the most potent congener. [16] TABLE 2 Anti-HBV Activity of PMEO-DAPy, (R)-PMPO-DAPy, and 5-Substituted PMEO-DAPy Derivatives [11,12] Compounds EC 50 (mg/mL) a [13,14] ANTI-ADENOVIRUS ACTIVITY [15] proved about 3-to 10fold more potent as anti-adenovirus agents than HPMPO-DAPy (Table 3).…”

Section: Anti-hbv Activitymentioning

confidence: 99%

Antiviral Potential of a New Generation of Acyclic Nucleoside Phosphonates, the 6-[2-(Phosphonomethoxy)alkoxy]-2,4-Diaminopyrimidines

Clercq

Andrei

Balzarini

et al. 2005

Nucleosides, Nucleotides & Nucleic Acids

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Three acyclic nucleoside phosphonates (ANPs) have been formally approved for clinical use in the treatment of 1) cytomegalovirus retinitis in AIDS patients (cidofovir, by the intravenous route), 2) chronic hepatitis B virus (HBV) infections (adefovir dipivoxil, by the oral route), and 3) human immunodeficiency virus (HIV) infections (tenofovir disoproxil fumarate, by the oral route). The activity spectrum of cidofovir {(S)- 1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine [(S)-HPMPC)]}, like that of (S)-HPMPA [(S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine) and (S)-HPMPDAP [(S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2, 6-diaminopurine), encompasses a broad spectrum of DNA viruses, including polyoma-, papilloma-, adeno-, herpes-, and poxviruses. Adefovir {9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)} and tenofovir [(R)-9-[2-(phosphonomethoxy) propyl]adenine [(R)-PMPA)]} are particularly active against retroviruses (ie., HIV) and hepadnaviruses (ie., HBV); additionally, PMEA also shows activity against herpes- and poxviruses. We have recently identified a new class of ANPs, namely 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines, named, in analogy with their alkylpurine counterparts, HPMPO-DAPy, PMEO-DAPy, and (R)-PMPO-DAPy. These compounds exhibit an antiviral activity spectrum and potency that is similar to that of (S)-HPMPDAP, PMEA, and (R)-PMPA, respectively. Thus, PMEO-DAPy and (R)-PMPO-DAPy, akin to PMEA and (R)-PMPA, proved particularly active against HIV- 1, HIV-2, and the murine retrovirus Moloney sarcoma virus (MSV). PMEO-DAPy and (R)-PMPO-DAPy also showed potent activity against both wild-type and lamivudine-resistant strains of HBV. HPMPO-DAPy was found to inhibit different poxviruses (ie., vaccinia, cowpox, and orf) at a similar potency as cidofovir. HPMPO-DAPy also proved active against adenoviruses. In vivo, HPMPO-DAPy proved equipotent to cidofovir in suppressing vaccinia virus infection (tail lesion formation) in immunocompetent mice and promoting healing of disseminated vaccinia lesions in athymic-nude mice. The 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines offer substantial potential for the treatment of a broad range of retro-, hepadna-, herpes-, adeno-, and poxvirus infections.

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Section: Anti-hbv Activitymentioning

confidence: 99%

Antiviral Potential of a New Generation of Acyclic Nucleoside Phosphonates, the 6-[2-(Phosphonomethoxy)alkoxy]-2,4-Diaminopyrimidines

Clercq

Andrei

Balzarini

et al. 2005

Nucleosides, Nucleotides & Nucleic Acids

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“…(S)-HPMPO−DAPy ( 16), an acyclic nucleoside phosphonate analogue similar to cidofovir (3), had broad-spectrum antiviral activity in inhibiting herpesviruses, retroviruses, RNA viruses, and poxviruses. 93 (S)-HPMPO−DAPy ( 16) inhibited VACV with an EC 50 of 19 μM. In cynomolgus monkeys (Macaca fascicularis) that were infected with a lethal dose of MPXV, (S)-HPMPO−DAPy (16) and cidofovir (3) showed comparable in vivo antiviral efficacy in reducing mortality and cutaneous monkeypox lesions when treatment was initiated 24 h post infection.…”

Section: Antivirals Against Orthopoxvirusesmentioning

confidence: 99%

An Overview of Antivirals against Monkeypox Virus and Other Orthopoxviruses

et al. 2023

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The current monkeypox outbreaks during the COVID-19 pandemic have reignited interest in orthopoxvirus antivirals. Monkeypox belongs to the Orthopoxvirus genus of the Poxviridae family, which also includes the variola virus, vaccinia virus, and cowpox virus. Two orally bioavailable drugs, tecovirimat and brincidofovir, have been approved for treating smallpox infections. Given their human safety profiles and in vivo antiviral efficacy in animal models, both drugs have also been recommended to treat monkeypox infection. To facilitate the development of additional orthopoxvirus antivirals, we summarize the antiviral activity, mechanism of action, and mechanism of resistance of orthopoxvirus antivirals. This perspective covers both direct-acting and host-targeting antivirals with an emphasis on drug candidates showing in vivo antiviral efficacy in animal models. We hope to speed the orthopoxvirus antiviral drug discovery by providing medicinal chemists with insights into prioritizing proper drug targets and hits for further development.

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“…Apart from that, an acyclic pyrimidine nucleoside phosphate named PMEO-DAPym represents the prototype compound of a novel class of pyrimidine acyclic nucleoside phosphonates that are recognized as a purine nucleotide [42]. In vitro experiments showed that even multi-drug resistant HBV strains remained sensitive to this compound [43,44]. Hence, this compound could represent a promising drug for treatment of HBV (and HIV) in the future.…”

Section: Nucleos(t)ide Analogues (Nucs)mentioning

confidence: 99%

HBV life cycle and novel drug targets

2011

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With up to 400 million affected people worldwide, chronic hepatitis B virus (HBV) infection is still a major health care problem. During the last decade, several novel therapeutic approaches have been developed and evaluated. In most regions of the world, interferon-α, and nucleos(t)ide analogues (NUCs) are currently approved. Despite major improvements, none of the existing therapies is optimal since viral clearance is rarely achieved. Recently, a better understanding of the HBV life cycle and the development of novel model systems of HBV infection have led to the development of novel antiviral strategies and drug targets. This review will focus on current and potential future drug targets in the HBV life cycle and strategies to modulate the virus-host interaction.

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6‐[2‐(Phosphonomethoxy)alkoxy]‐2,4‐diaminopyrimidines: A New Class of Acyclic Pyrimidine Nucleoside Phosphonates with Antiviral Activity

Abstract: PANNECOUQUE, C.; NAESENS, L.; ANDREI, G.; SNOECK, R.; DE CLERCQ, E.; HOCKOVA, D.; HOLY, A.; Nucleosides, Nucleotides Nucleic Acids 23 (2004) 8-9, 1321-1327; Rega Inst. Med. Res., Kathol. Univ. Leuven, B-3000 Leuven, Belg.; Eng.) -Lindner 10-222

Cited by 3 publications

References 1 publication

Antiviral Potential of a New Generation of Acyclic Nucleoside Phosphonates, the 6-[2-(Phosphonomethoxy)alkoxy]-2,4-Diaminopyrimidines

Antiviral Potential of a New Generation of Acyclic Nucleoside Phosphonates, the 6-[2-(Phosphonomethoxy)alkoxy]-2,4-Diaminopyrimidines

An Overview of Antivirals against Monkeypox Virus and Other Orthopoxviruses

HBV life cycle and novel drug targets

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