A Novel Class of Phosphonate Nucleosides. 9-[(1-Phosphonomethoxycyclopropyl)methyl]guanine as a Potent and Selective Anti-HBV Agent

Choi, Jong-Ryoo; Cho, Dong-Gyu; Roh, Kee Y.; Hwang, Jae‐Taeg; Ahn, Sinbyoung; Jang, Hyun Soo; Cho, None Woo-Young; Kim, Kyong W.; Cho, Young-Gyo; Kim, Jeongmin; Kim, Yong-Zu

doi:10.1021/jm0305265

Cited by 62 publications

(33 citation statements)

References 16 publications

(51 reference statements)

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“…However, the guanine analogue, PMCG (23) is several folds more potent than adefovir. This series of compounds is reported to be low cytotoxic [69].…”

Section: Structure-activity Relationship Of Adefovir Analogsmentioning

confidence: 93%

Nucleoside Analogs as Anti-HBV Agents

Zhou¹,

Littler

2006

CTMC

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Chronic hepatitis B virus (HBV) infection affects about 400 million people worldwide. The development of nucleoside analogs that inhibit HBV polymerase provides an important approach for treating HBV infection. The approval of lamivudine, adefovir and entecavir represents a cornerstone of hepatitis B therapy. However, the challenges from the resistance and the off-therapy viral rebound are still unmet, and there is a need of developing new therapeutic agents. This review will discuss the structure-activity relationship of the most significant anti-HBV nucleoside analogs and the latest development in the field.

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“…However, the guanine analogue, PMCG (23) is several folds more potent than adefovir. This series of compounds is reported to be low cytotoxic [69].…”

Section: Structure-activity Relationship Of Adefovir Analogsmentioning

confidence: 93%

Nucleoside Analogs as Anti-HBV Agents

Zhou¹,

Littler

2006

CTMC

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“…Even though it is frequently regarded as a “adefovir-like” nucleotide, it is considered, at least by some, as a representative of a novel class of phosphonate nucleosides that blocks HBV replication with an excellent potency (EC 50 of 0.5 μM) in HepG2 2.2.15 cells (Choi et al 2004). LB-80380 did not show any cytotoxicity in several human cell lines in concentrations up to 2000 times of that required for an EC50 for HBV inhibition.…”

Section: Lb-80380mentioning

confidence: 99%

“…This, however, requires further evaluation in light of the unexpected activity of entecavir against HIV (McMahon et al 2007). Furthermore, in its oral form, PMCDG dipivoxil, excellent efficacy was achieved in HBV infected woodchucks at 5 mg/kg/d (Choi et al 2004). …”

Section: Lb-80380mentioning

confidence: 99%

The treatment of chronic hepatitis B: Focus on adefovir-like antivirals

Tillmann

2008

TCRM

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Several options for the treatment of hepatitis B have been licensed in the last years: interferon, pegylated interferon, lamivudine, adefovir, entecavir, and telbivudine. In addition tenofovir has been licensed in the EU and is expected to be licensed in the USA in 2008. The antivirals can be divided into “lamivudine-like” and “adefovir-like”, which clinically differ in their capacity to induce “YMDD” mutants, which are the hallmark of lamivudine resistance. The differing resistance profile makes them good combination partners, even in the absence of synergy in antiviral potency.

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“…The stable phosphonate linkage prevents the hydrolysis by esterases back to the parent nucleosides which would reduce their antiviral effects. Compound 21 blocks hepatitis B virus replication with excellent potency (EC 50 = 0.5 µM), and has been modified to give the orally available drug candidate PMCDG Dipivoxil (22), currently undergoing phase II clinical studies [46]. In a similar vein, phosphonate analogues of nucleoside monophosphates such as compound 23 have shown substantial inhibition of inosine 5'-monophosphate dehydrogenases (low micromolar K i values) [47].…”

Section: Non-phosphotyrosine Targetsmentioning

confidence: 99%

Phosphate Isosteres in Medicinal Chemistry

Rye

Baell

2005

CMC

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The phosphate group is at the heart of an enormous number of biological processes. The simple phosphorylation or dephosphorylation of a protein can have a wide range of consequences, including effects on its biological activity, its interaction with other proteins, and on its subcellular location. Abnormal levels of protein phosphorylation have been linked to a wide range of diseases including cancer and diabetes. Consequently, proteins that recognise the phosphate moiety have become an attractive target for therapeutic development. The most prevalent medicinal chemistry research examines the interactions of phosphorylated tyrosine residues; however, the role of phosphate groups on serine or threonine residues, in nucleotides, DNA and RNA, on sugars, and lipid mediators such as lysophosphatidic acid should not be overlooked. Investigations have focused on the non-catalytic phosphotyrosine-recognising domains such as Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains, as well as catalytic proteins such as protein tyrosine phosphatase 1B (PTP1B). The utilisation of the phosphate moiety as part of an inhibitor is severely limited by the enzymatic lability and poor cellular bioavailability of this highly charged recognition element. The development of phosphate isosteres attempts to address these issues by introducing a non-scissile bond and utilizing groups with less charge that are still able to interact favourably with the target protein in much the same way as the phosphate group does. Many phosphate mimics retain the phosphorus atom such as in the highly successful fluoromethylenephosphonates, whereas others have lost the tetrahedral phosphate geometry and are based on the combination of one or more carboxylate groups that generally reduce the overall charge of the molecule. This review focuses on the recent developments and the use of phosphate isosteres in medicinal chemistry, covering roughly the past four years.

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A Novel Class of Phosphonate Nucleosides. 9-[(1-Phosphonomethoxycyclopropyl)methyl]guanine as a Potent and Selective Anti-HBV Agent

Cited by 62 publications

References 16 publications

Nucleoside Analogs as Anti-HBV Agents

Nucleoside Analogs as Anti-HBV Agents

The treatment of chronic hepatitis B: Focus on adefovir-like antivirals

Phosphate Isosteres in Medicinal Chemistry

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