The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2′-α-chloro-2′-β-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors

Alexandre, François-René; Badaroux, Eric; Bilello, John P.; Bot, Stéphanie; Bouisset, Tony; Brandt, Guillaume; Cappelle, Sylvie; Chapron, Christopher; Chaves, Dominique; Convard, Thierry; Counor, Clément; Costa, Daniel Da; Dukhan, David; Gay, Marion; Gosselin, Gilles; Griffon, Jean-François; Gupta, Kusum; Hernandez-Santiago, Brenda I.; Colla, Massimiliano La; Lioure, Marie-Pierre; Milhau, Julien; Paparin, Jean-Laurent; Peyronnet, Jérôme; Parsy, Christophe; Rouvière, Claire Pierra; Rahali, Houcine; Rahali, Rachid; Salanson, Aurélien; Seifer, Maria; Serra, Ilaria; Standring, David N.; Surleraux, Dominique; Dousson, Cyril B.

doi:10.1016/j.bmcl.2017.08.029

Cited by 29 publications

(11 citation statements)

References 30 publications

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“…Incubation of these three compounds with CatA for 18 h resulted with no hydrolysis of MK-3682 and S P isomer and complete metabolism of sofosbuvir. 220 The most recent data from the two Phase II studies on efficacy and safety of uprifosbuvir together with grazoprevir and ruzasvir, a HCV nonstructural protein 5A inhibitor, either with or without RBV for 16 and 24 weeks, respectively in patients who had previously failed an NS5A inhibitor-containing treatment, showed that this triple-combination therapy was safe and highly effective. 221 Several other clinical trials Phase I/II studies for MK-3682 were on-going in a combination therapy with RBV or non-nucleoside agents such as grazoprevir, elbasvir, and ruzasvir.…”

Section: Protides In Clinical Use or In Clinical Development As Antivmentioning

confidence: 99%

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Ślusarczyk

Serpi

Pertusati

2018

Antivir Chem Chemother

105

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Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5'-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5'-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5'-monophosphate, which is further transformed to the active 5'-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan's research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents.

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Section: Protides In Clinical Use or In Clinical Development As Antivmentioning

confidence: 99%

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Ślusarczyk

Serpi

Pertusati

2018

Antivir Chem Chemother

105

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“…吉利德科学(Gilead Sciences)的 Cho 等 [22] 报道了抗丙肝候选药物 GS-6620 ( 12 孙宏斌和王广基等 [25] Uprifosbuvir (4)是 IDENIX 和默沙东开发的一款抗 HCV 试验药物 [26] , 其侧链的磷原子和丙氨酸酯 α-碳构型均为(R), 较为独特. Simmons 等 [27] [28] , uprifosbuvir/ruzasvir 联合疗法对 HCV GT1, GT2, GT4, GT5 和 GT6 五种基因型的患者具有显著疗效, 且总体耐受度好.…”

Section: 往往并不理想这可被归结为以下原因: (I)磷原子有空unclassified

Asymmetric Synthesis of Prodrug Nucleotides (ProTides): Construction of the P-Stereogenic Centers

Liu¹,

Cheng²,

Hong³

2020

Chin. J. Org. Chem.

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As an antivirus drug, remdesivir is currently in clinical studies for the treatment of COVID-19. Remdesivir is a prodrug originally developed by Gilead for the treatment of Ebola. The prodrug nucleotide (ProTide) technology is a prodrug-designing strategy developed by McGuigan and co-workers, in which a phosphoramidate side-chain is covalently attached to the hydroxy group of a drug molecule in order to enhance the cell permeability and metabolic activation efficiency. This approach has proved to be very successful in the identification of nucleoside analogues with antiviral or antitumor activities. It is also adapted in the application of non-nucleoside agents, such as neurodegeneration therapeutics, further demonstrating its usefulness in drug discovery. The chirality of the pentavalent phosphorous plays a significant role in the bioactivity of a ProTide molecule. Therefore, the efficient synthesis of such chemical scaffold in a highly enantioselective manner is very desirable and has intrigued great interests from both academia and pharmaceutical industry. In this review, based on the reactions employing optically pure P(V) precursors or P-racemic P(V) precursors, the recent advances on the stereoselective assembly of ProTide compounds are summarized. Various innovative strategies, including (dynamic) kinetic resolutions, were implemented to construct the vital P-stereogenic center with high regio-and stereo-selectivity. It is notable that several methods could be performed at kilogram scale, which are highlighted to showcase their practical values in the process chemistry. The asymmetric synthesis of enantiopure phosphoramidate precursors is illustrated in detail which will be informative for future drug development. Moreover, the clinical performance of some investigational ProTide drugs is also briefly discussed.

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“…]oxy]carbonyl]-3-methyl-L-valyl-(4R)-4-hydroxy-L-prolyl-(1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-ethenylcyclopropanecarboxamide cyclic (1¡2)-ether, an NS3/4A protease inhibitor, was prepared as reported previously (46,60). 3R,4R,5R)-4-chloro-5-(2,4-dioxopyrimidin-1-yl)-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate, is an NS5B polymerase prodrug (57). As reported previously, UPR has weak activity in Huh7 replicon cells as a result of low carboxylesterase 1 (CES-1) and also cytochrome P450 (CYP) 3A4 expression levels; hence, a cellular active surrogate that generates the same active triphosphate and bears the L-alanine phosphoramidate prodrug was used in this study.…”

Section: Compounds Ruzasvir (Rzr) Nn=-[[(6s)-6-(2-cyclopropyl-5-thmentioning

confidence: 99%

In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A

Asante‐Appiah

Liu

Curry

et al. 2018

Antimicrob Agents Chemother

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Inhibition of NS5A has emerged as an attractive strategy to intervene in hepatitis C virus (HCV) replication. Ruzasvir (formerly MK-8408) was developed as a novel NS5A inhibitor to improve upon the potency and barrier to resistance of early compounds. Ruzasvir inhibited HCV RNA replication with 50% effective concentrations (ECs) of 1 to 4 pM in Huh7 or Huh7.5 cells bearing replicons for HCV genotype 1 (GT1) to GT7. The antiviral activity was modestly (10-fold) reduced in the presence of 40% normal human serum. The picomolar potency in replicon cells extended to sequences of clinical isolates available in public databases that were synthesized and tested as replicons. In GT1a, ruzasvir inhibited common NS5A resistance-associated substitutions (RASs), with the exception of M28G. resistance selection studies identified pathways with certain amino acid substitutions at residues 28, 30, 31, and 93 across genotypes. Substitutions at position 93 were more common in GT1 to -4, while changes at position 31 emerged frequently in GT5 and -6. With the exception of GT4, the reintroduction of selected RASs conferred a ≥100-fold potency reduction in the antiviral activity of ruzasvir. Common RASs from other classes of direct-acting antiviral agents (DAAs) did not confer cross-resistance to ruzasvir. The interaction of ruzasvir with an NS3/4A protease inhibitor (grazoprevir) and an NS5B polymerase prodrug (uprifosbuvir) was additive to synergistic, with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir.

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The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2′-α-chloro-2′-β-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors

Cited by 29 publications

References 30 publications

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Asymmetric Synthesis of Prodrug Nucleotides (ProTides): Construction of the P-Stereogenic Centers

In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A

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