ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Thiophenes/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Regulation/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cyclohexanols/chemistry , Cyclohexanols/pharmacology , Dose-Response Relationship, Drug , Hepacivirus/enzymology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.
Subject(s)
Autoimmune Diseases/drug therapy , Heterocyclic Compounds, 2-Ring/chemistry , Janus Kinase 3/antagonists & inhibitors , Valine/analogs & derivatives , Animals , Cell Line , Databases, Chemical , Dogs , Female , Graft vs Host Disease/drug therapy , Graft vs Host Disease/immunology , Haplorhini , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Janus Kinase 2/chemistry , Janus Kinase 3/chemistry , Male , Mice , Mice, Inbred BALB C , Mice, Inbred CBA , Microsomes, Liver/metabolism , Models, Molecular , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Valine/chemistry , Valine/pharmacokinetics , Valine/pharmacologyABSTRACT
In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.
Subject(s)
Antiviral Agents/chemistry , Aza Compounds/chemistry , Indoles/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Biological Availability , Dogs , Drug Resistance, Viral , Indoles/chemical synthesis , Indoles/pharmacology , Influenza A virus/drug effects , Influenza A virus/physiology , Madin Darby Canine Kidney Cells , Male , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Orthomyxoviridae Infections/drug therapy , Rats , Species Specificity , Stereoisomerism , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
[reaction: see text] Condensation of a benzopyranonphthalide with Michael acceptors provides an efficient, general method for regiospecific preparation of xanthones as well as linear and angular polycyclic aromatic systems containing a xanthone fragment.
Subject(s)
Xanthones/chemical synthesis , Benzofurans/chemistry , Benzopyrans/chemistry , StereoisomerismABSTRACT
[reaction: see text] Condensation of the phthalide sulfide with an ortho-quinone monoketal was employed as a key step in the first total synthesis of a derivative of (+/-)-PD 116740.
