Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320

Parsy, Christophe; Alexandre, François-René; Bidau, Valérie; Bonnaterre, Florence; Brandt, Guillaume; Caillet, Catherine; Cappelle, Sylvie; Chaves, Dominique; Convard, Thierry; Derock, Michel; Gloux, Damien; Griffon, Yann; Lallos, L.; Leroy, Frédéric; Liuzzi, Michel; Loi, Anna-Giulia; Moulat, Laure; Montaldo, Chiara; Rahali, Houcine; Roques, Virginie; Rosinovsky, Elodie; Savin, Simon; Seifer, Maria; Standring, David N.; Surleraux, Dominique

doi:10.1016/j.bmcl.2015.09.009

Cited by 23 publications

(11 citation statements)

References 28 publications

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“…The pyrimidine based sulfonamide (26) analogues were also tested for The benzidine prolinamide derivatives exerted anti-HCV properties against genotypes 2a and 1b demonstrated its potency towards genotype 1b (EC 50 ¼ 0.028 nM). Other heterocyclic molecules (27,28) (Fig. 9) [50] are showed good result against HCV (EC 50 ¼ 0.26 nM, 6 nM and IC 50 ¼ 5 nM) infections respectively [51].…”

Section: Nucleoside Non-nucleoside and Protease Inhibitors As Anti-hmentioning

confidence: 95%

A review on HCV inhibitors: Significance of non-structural polyproteins

Ganta¹,

Gedda

Rathnakar

et al. 2019

European Journal of Medicinal Chemistry

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a b s t r a c tHepatitis C virus (HCV) mortality and morbidity is a world health misery with an approximate 130e150 million chronically HCV tainted and suffering individuals and it initiate critical liver malfunction like cirrhosis, hepatocellular carcinoma or liver HCV cancer. HCV NS5B protein one of the best studied therapeutic target for the identification of new drug candidates to be added to the combination or multiple combination medication recently approved. During the past few years, NS5B has thus been an important object of attractive medicinal chemistry endeavors, which induced to the surfacing of betrothal preclinical drug molecules. In this scenario, the current review set limit to discuss research published on NS5B and few other therapeutic functional inhibitors concentrating on hit investigation, hit to lead optimization, ADME parameters evaluation, and the SAR data which was out for each compound type and similarity taken into consideration. The discussion outlined in this specific review will surly helpful and vital tool for those medicinal chemists investigators working with HCV research programs mainly pointing on NS5B and set broad spectrum identification of creative anti HCV compounds. This mini review also tells each and every individual compound ability related how much they are active against NS5B and few other targets.

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Section: Nucleoside Non-nucleoside and Protease Inhibitors As Anti-hmentioning

confidence: 95%

A review on HCV inhibitors: Significance of non-structural polyproteins

Ganta¹,

Gedda

Rathnakar

et al. 2019

European Journal of Medicinal Chemistry

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“…Understanding of flavivirus proteins and other RNA viruses has benefited from the EU funded project VIZIER 77 , in particular several West Nile virus, dengue virus and other flavivirus structures of NS3 or NS5 were solved during this project and allosteric inhibitor sites were identified on NS5 78 . Multiple pharmaceutical companies have worked on this target for HCV leading to clinical candidates like IDX320 79 , danoprevir (ITMN-191/R7227) 80 , GS-9256 81 and others 82 , 83 . The only HCV protease targeting FDA approved drug is simeprevir, TMC435 84 , 85 and its use is avoided in pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Illustrating and homology modeling the proteins of the Zika virus

Ekins

John²,

Neves

et al. 2016

F1000Res

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The Zika virus (ZIKV) is a flavivirus of the family Flaviviridae, which is similar to dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barré syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it either in vitro or in vivo. ZIKV therefore epitomizes a neglected disease. Several suggested steps have been proposed which could be taken to initiate ZIKV antiviral drug discovery using both high throughput screens as well as structure-based design based on homology models for the key proteins. We now describe preliminary homology models created for NS5, FtsJ, NS4B, NS4A, HELICc, DEXDc, peptidase S7, NS2B, NS2A, NS1, E stem, glycoprotein M, propeptide, capsid and glycoprotein E using SWISS-MODEL. Eleven out of 15 models pass our model quality criteria for their further use. While a ZIKV glycoprotein E homology model was initially described in the immature conformation as a trimer, we now describe the mature dimer conformer which allowed the construction of an illustration of the complete virion. By comparing illustrations of ZIKV based on this new homology model and the dengue virus crystal structure we propose potential differences that could be exploited for antiviral and vaccine design. The prediction of sites for glycosylation on this protein may also be useful in this regard. While we await a cryo-EM structure of ZIKV and eventual crystal structures of the individual proteins, these homology models provide the community with a starting point for structure-based design of drugs and vaccines as well as a for computational virtual screening.

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“…However,c ompound 229 was implicated as the source of liver toxicity observed in clinical studies and fur-ther development of the compound was abandoned ( Figure 20). [84][85][86][87][88] The discovery synthesis of 228 that is summarized in Scheme 27 reliesu pon aM itsunobu reaction between preformed macrocyclic 4-hydroxyproline 231 and hydroxyquinoline 230;t his is an approach that allowsac onvenient and expansives urvey of both the P2* and P1' elements. [84,85] An optimized process used to preparet he quantities of 228 necessary to complete preclinicale valuationi sd epicted in Schemes28a nd 29.…”

Section: Idx316and Idx320mentioning

confidence: 99%

“…[84][85][86][87][88] The discovery synthesis of 228 that is summarized in Scheme 27 reliesu pon aM itsunobu reaction between preformed macrocyclic 4-hydroxyproline 231 and hydroxyquinoline 230;t his is an approach that allowsac onvenient and expansives urvey of both the P2* and P1' elements. [84,85] An optimized process used to preparet he quantities of 228 necessary to complete preclinicale valuationi sd epicted in Schemes28a nd 29. Thesynthesis of the P1-P1' moiety 233 involves an initial Boc protection of the amine of commercially available 234 to give an ester that wass aponified to afford acid 235 in quantitative yield (Scheme 28).…”

Section: Idx316and Idx320mentioning

confidence: 99%

“…The synthesis of 229 took advantage of knowledge gained from the scaling up of 228 and began with coupling of the ptoluenesulfonic acid salt of N-methylhex-5-en-1-amine( 244) with CDI, which afforded imidazolyl carboxamide 245 in quantitative yield (Scheme 30). [84,85] However,a ttempts to couple 245 directly with methyl (2S,4R)-4-hydroxypiperidine-2-carboxylate (247)w ere unsuccessful, producing only trace amounts of urea 248.T his necessitatedt he activation of 245 by methylation (MeI/MeCN) to afford 246,w hich was coupled with the HCl salt of 247 in THFi nt he presence of Et 3 Na st he base to provide urea 248 in 71 %y ield. The P2* quinoline 238 wasi ntroducedu nder standard Mitsunobur eactionc onditions and proceeded with inversiono fc onfiguration at the piperidine ring.…”

Section: Idx316and Idx320mentioning

confidence: 99%

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Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Mei

Han

White

et al. 2020

Chemistry A European J

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Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor‐made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man‐made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

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Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320

Cited by 23 publications

References 28 publications

A review on HCV inhibitors: Significance of non-structural polyproteins

A review on HCV inhibitors: Significance of non-structural polyproteins

Illustrating and homology modeling the proteins of the Zika virus

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

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