VX-222 (VCH-222, Lomibuvir)

VX-222, a derivative of thiophene-2-carboxylic acid, is a potent non-nucleoside inhibitor (NNI) of the hepatitis C virus (HCV) RNA polymerase, an enzyme regulating RNA synthesis by a de novo-initiated mechanism or by extension from a primed template, that binds to the thumb II allosteric pocket of HCV RNA-dependent RNA polymerase with hydrophobical interactions between the 4-methycyclohexanoyl group of VX-222 and L412, M423 and I482 of thumb II domain. VX-222 exhibits preferential inhibition against primer-dependent RNA synthesis rather than de novo-initiated RNA synthesis with 50% inhibition concentration IC₅₀ values ranging from 0.011 to >5 μM in five different templates of RNA synthesis.

Reference

Yi G, Deval J, Fan B, Cai H, Soulard C, Ranjith-Kumar CT, Smith DB, Blatt L, Beigelman L, Kao CC. Biochemical study of the comparative inhibition of hepatitis C virus RNA polymerase by VX-222 and filibuvir. Antimicrob Agents Chemother. 2012 Feb;56(2):830-7. doi: 10.1128/AAC.05438-11. Epub 2011 Dec 5.

Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates.[Pubmed:28197321]

ACS Med Chem Lett. 2017 Jan 31;8(2):251-255.

Lomibuvir (1) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound 2, a molecule with comparable potency and an improved physicochemical profile relative to 1. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by 12f, provided 3-5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure-activity relationships, in vitro ADME characterization, and in vivo evaluation of this novel series are discussed.

Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles.[Pubmed:27366941]

J Med Chem. 2016 Jul 14;59(13):6293-302.

The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound 23, a compound with comparable potency and improved physicochemical properties.

Discontinued drugs in 2012 - 2013: hepatitis C virus infection.[Pubmed:25384989]

Expert Opin Investig Drugs. 2015 Feb;24(2):239-51.

INTRODUCTION: Hepatitis C virus (HCV) chronically infects about 150 million people worldwide. Antiviral treatment can stop and even reverse the progression of the disease. Several antivirals have been developed. However, about 10,000 compounds are tested for each drug that eventually reaches the market. It would be useful to learn from these failures, for example, by reporting the candidate drugs that were discontinued and the reason for discontinuation. AREAS COVERED: This article focuses on the anti-HCV drug candidates discontinued between 1 January 2012 and 1 January 2014. EXPERT OPINION: In detail, 17 drugs were discontinued. Of these: 10 were NS5B inhibitors, 3 were NS5A inhibitors, 2 were immunostimulants, 1 was a therapeutic and prophylactic vaccine and 1 an NS3 inhibitor. Only 3 candidates were discontinued in the preclinical phase, and 14 were discontinued during clinical development (8 in Phase II and 6 in Phase I). Most discontinuations were attributed to corporate strategic decisions. The authors believe that learning from HCV drug development failures will help pharmaceutical companies and researchers to develop better strategies for the future. It is therefore important that this information is made available.

In vitro antiviral activity and preclinical and clinical resistance profile of miravirsen, a novel anti-hepatitis C virus therapeutic targeting the human factor miR-122.[Pubmed:25385103]

Antimicrob Agents Chemother. 2015 Jan;59(1):599-608.

Miravirsen is a beta-D-oxy-locked nucleic acid-modified phosphorothioate antisense oligonucleotide targeting the liver-specific microRNA-122 (miR-122). Miravirsen demonstrated antiviral activity against hepatitis C virus (HCV) genotype 1b replicons with a mean 50% effective concentration (EC50) of 0.67 muM. No cytotoxicity was observed up to the highest concentration tested (>320 muM) in different cell culture models, yielding a therapeutic index of >/= 297. Combination studies of miravirsen with interferon alpha2b, ribavirin, and nonnucleoside (VX-222) and nucleoside (2'-methylcytidine) inhibitors of NS5B, NS5A (BMS-790052), or NS3 (telaprevir) indicated additive interactions. Miravirsen demonstrated broad antiviral activity when tested against HCV replicons resistant to NS3, NS5A, and NS5B inhibitors with less than 2-fold reductions in susceptibility. In serial passage studies, an A4C nucleotide change was observed in the HCV 5' untranslated region (UTR) from cells passaged in the presence of up to 20 muM (40-fold the miravirsen EC50 concentration) at day 72 of passage but not at earlier time points (up to 39 days of passage). Likewise, a C3U nucleotide change was observed in the HCV 5'UTR from subjects with viral rebound after the completion of therapy in a miravirsen phase 2 clinical trial. An HCV variant constructed to contain the A4C change was fully susceptible to miravirsen. A C3U HCV variant demonstrated overall reductions in susceptibility to miravirsen but was fully susceptible to all other anti-HCV agents tested. In summary, miravirsen has demonstrated broad antiviral activity and a relatively high genetic barrier to resistance. The identification of nucleotide changes associated with miravirsen resistance should help further elucidate the biology of miR-122 interactions with HCV. (The clinical trial study has been registered at ClinicalTrials.gov under registration no. NCT01200420).

Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase.[Pubmed:28621755]

Viruses. 2017 Jun 16;9(6). pii: v9060151.

Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophysical techniques and a novel biosensor-based real-time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compounds interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure analysis revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compounds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a.

VX-222 (VCH-222) is a novel, potent and selective inhibitor of HCV polymerase with IC50 of 0.94-1.2 μM, 15.3-fold less effective for mutant M423T, and 108-fold less effective for mutant I482L.

VX-222 (VCH-222, Lomibuvir),1026785-59-0,VCH-222,Natural Products,HCV Protease, buy VX-222 (VCH-222, Lomibuvir) , VX-222 (VCH-222, Lomibuvir) supplier , purchase VX-222 (VCH-222, Lomibuvir) , VX-222 (VCH-222, Lomibuvir) cost , VX-222 (VCH-222, Lomibuvir) manufacturer , order VX-222 (VCH-222, Lomibuvir) , high purity VX-222 (VCH-222, Lomibuvir)