This report describes a number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens. The compounds identified by such substructural features are not recognized by filters commonly used to identify reactive compounds. Even though these substructural features were identified using only one assay detection technology, such compounds have been reported to be active from many different assays. In fact, these compounds are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.

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New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays

For many decades, the design of new nucleoside analogs as potential therapeutic agents focused on both sugar and nucleobase modifications. These nucleoside analogs rely on cellular kinases to undergo stepwise addition of phosphate groups to form the corresponding active nucleoside triphosphate to express their therapeutic effect.1 However, nucleosides triphosphates cannot be considered as viable drug candidates as they usually have poor chemical stability along with high polarity that hinders them from transporting across cell membranes. Within the nucleoside analog phosphate activation process, the first phosphorylation has often been identified as the limiting step, which led medicinal chemists to prepare stable “protected” monophosphate nucleosides capable of delivering nucleoside monophosphates intracellularly. These nucleoside monophosphate prodrugs are designed to efficiently cross the biological barriers (as opposed to nucleoside monophosphates; Figure ​Figure1,1, eq 1) and reach the targeted cells or tissues. Once inside the cell, the biolabile protecting groups are then degraded enzymatically and/or chemically, releasing the free nucleoside analog in the monophosphate form, which can often efficiently express its therapeutical potency by intracellular conversion to the corresponding nucleoside triphosphate (Figure ​(Figure1,1, eq 2).




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Figure 1


Mechanism of action of nucleoside monophosphate prodrugs.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.

Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase

An enantiomer, diastereoisomer or tautomer of a compound, represented by formula I: wherein A, B, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined herein, or a salt or ester thereof, as an inhibitor of HCV NS5B polymerase.

Viral Polymerase Inhibitors

Synthesis and antiviral activity of new pyrazole and thiazole derivatives

Novel thiazolones as HCV NS5B polymerase allosteric inhibitors: Further designs, SAR, and X-ray complex structure

Parallel synthesis of 5-cyano-6-aryl-2-thiouracil derivatives as inhibitors for hepatitis C viral NS5B RNA-dependent RNA polymerase.

Various 2'-modified nucleoside analogs and corresponding prodrugs are provided, and particularly contemplated methods of use include use as antiviral agents, and especially as antiviral agents against HCV.

Sugar modified nucleosides as viral replication inhibitors

Various 2′-beta-methyl-6-substituted adenosine analogs (including 2,6-disubstituted adenosine, 8-aza-6-substituted adenosine, and 2-aza-6-substituted adenosine) are prepared by conventional and combinatorial library approaches. Contemplated compounds are particularly useful as therapeutic agents, and especially as antiviral agents.

Yili Ding

Papers

Novel thiazolones as HCV NS5B polymerase allosteric inhibitors: Further designs, SAR, and X-ray complex structure

Parallel synthesis of 5-cyano-6-aryl-2-thiouracil derivatives as inhibitors for hepatitis C viral NS5B RNA-dependent RNA polymerase.

Sugar modified nucleosides as viral replication inhibitors

2'-beta-modified-6-substituted adenosine analogs and their use as antiviral agents

Parallel synthesis of pteridine derivatives as potent inhibitors for hepatitis C virus NS5B RNA-dependent RNA polymerase.