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1.
J Med Chem ; 59(13): 6293-302, 2016 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-27366941

RESUMEN

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.


Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Tiofenos/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Ciclohexanoles/química , Ciclohexanoles/farmacología , Relación Dosis-Respuesta a Droga , Hepacivirus/enzimología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos
3.
Bioorg Med Chem Lett ; 25(4): 936-9, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25595681

RESUMEN

The discovery of C2-symmetric bis-thienoimidazoles HCV NS5A inhibitors is herein reported. Two straightforward approaches to access the requisite diyne and biphenyl linker moieties are described. This study revealed the paramount importance of the aromatic character of the linker to achieve high genotype 1a potency.


Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Imidazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Imidazoles/química
4.
Bioorg Med Chem Lett ; 25(4): 948-51, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25577039

RESUMEN

Inhibitors of the HCV NS5A nonstructural protein are showing promising clinical potential in the treatment of hepatitis C when used in combination with other direct-acting antiviral agents. Current NS5A clinical candidates such as daclatasvir, ledipasvir, and ombitasvir share a common pharmacophore that features a pair of (S)-methoxycarbonylvaline capped pyrrolidines linked to various cores by amides, imidazoles and/or benzimidazoles. In this Letter, we describe the evaluation of NS5A inhibitors which contain alternative heteroaromatic replacements for these amide mimetics. The SAR knowledge gleaned in the optimization of scaffolds containing benzoxazoles was parlayed toward the identification of potent NS5A inhibitors containing other heteroaromatic replacements such as indoles and imidazopyridines.


Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 25(4): 944-7, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25577041

RESUMEN

The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons. Our SAR exploration of 4-substituted pyrrolidines revealed that the subtle inclusion of a 4-methyl group could profoundly increase genotype 1a potency in multiple scaffold classes.


Asunto(s)
Antivirales/farmacología , Bencimidazoles/farmacología , Pirrolidinas/farmacología , Proteínas no Estructurales Virales/efectos de los fármacos , Antivirales/química , Bencimidazoles/química , Genotipo , Pirrolidinas/química
6.
ACS Med Chem Lett ; 5(3): 240-3, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24900811

RESUMEN

The discovery of potent thienoimidazole-based HCV NS5A inhibitors is herein reported. A novel method to access the thienoimidazole [5,5]-bicyclic system is disclosed. This method gave access to a common key intermediate (6) that was engaged in Suzuki or Sonogashira reactions with coupling partners bearing different linkers. A detailed study of the structure-activity relationship (SAR) of the linkers revealed that aromatic linkers with linear topologies are required to achieve high potency for both 1a and 1b HCV genotypes. Compound 20, with a para-phenyl linker, was identified as a potential lead displaying potencies of 17 and 8 pM against genotype 1a and 1b replicons, respectively.

7.
J Chem Inf Model ; 48(4): 902-9, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18341269

RESUMEN

HCV NS5B polymerase is a validated target for the treatment of hepatitis C, known to be one of the most challenging enzymes for docking programs. In order to improve the low accuracy of existing docking methods observed with this challenging enzyme, we have significantly modified and updated F itted 1.0, a recently reported docking program, into F itted 1.5. This enhanced version is now applicable to the virtual screening of compound libraries and includes new features such as filters and pharmacophore- or interaction-site-oriented docking. As a first validation, F itted 1.5 was applied to the testing set previously developed for F itted 1.0 and extended to include hepatitis C virus (HCV) polymerase inhibitors. This first validation showed an increased accuracy as well as an increase in speed. It also shows that the accuracy toward HCV polymerase is better than previously observed with other programs. Next, application of F itted 1.5 to the virtual screening of the Maybridge library seeded with known HCV polymerase inhibitors revealed its ability to recover most of these actives in the top 5% of the hit list. As a third validation, further biological assays uncovered HCV polymerase inhibition for selected Maybridge compounds ranked in the top of the hit list.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Ligandos
8.
J Mol Biol ; 361(1): 33-45, 2006 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-16828488

RESUMEN

The RNA-dependent RNA polymerase (NS5B) from hepatitis C virus (HCV) is a key enzyme in HCV replication. NS5B is a major target for the development of antiviral compounds directed against HCV. Here we present the structures of three thiophene-based non-nucleoside inhibitors (NNIs) bound non-covalently to NS5B. Each of the inhibitors binds to NS5B non-competitively to a common binding site in the "thumb" domain that is approximately 35 Angstroms from the polymerase active site located in the "palm" domain. The three compounds exhibit IC(50) values in the range of 270 nM to 307 nM and have common binding features that result in relatively large conformational changes of residues that interact directly with the inhibitors as well as for other residues adjacent to the binding site. Detailed comparisons of the unbound NS5B structure with those having the bound inhibitors present show that residues Pro495 to Arg505 (the N terminus of the "T" helix) exhibit some of the largest changes. It has been reported that Pro495, Pro496, Val499 and Arg503 are part of the guanosine triphosphate (GTP) specific allosteric binding site located in close proximity to our binding site. It has also been reported that the introduction of mutations to key residues in this region (i.e. Val499Gly) ablate in vivo sub-genomic HCV RNA replication. The details of NS5B polymerase/inhibitor binding interactions coupled with the observed induced conformational changes provide new insights into the design of novel NNIs of HCV.


Asunto(s)
Inhibidores Enzimáticos/metabolismo , Hepacivirus/enzimología , Hidrocarburos Policíclicos Aromáticos/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Hepacivirus/efectos de los fármacos , Unión Proteica , ARN Polimerasa Dependiente del ARN/metabolismo , Proteínas no Estructurales Virales/química
9.
J Biol Chem ; 280(18): 18202-10, 2005 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-15746101

RESUMEN

Crystal structures of the RNA-dependent RNA polymerase genotype 2a of hepatitis C virus (HCV) from two crystal forms have been determined. Similar to the three-dimensional structures of HCV polymerase genotype 1b and other known polymerases, the structures of the HCV polymerase genotype 2a in both crystal forms can be depicted in the classical right-hand arrangement with fingers, palm, and thumb domains. The main structural differences between the molecules in the two crystal forms lie at the interface of the fingers and thumb domains. The relative orientation of the thumb domain with respect to the fingers and palm domains and the beta-flap region is altered. Structural analysis reveals that the NS5B polymerase in crystal form I adopts a "closed" conformation that is believed to be the active form, whereas NS5B in crystal form II adopts an "open" conformation and is thus in the inactive form. In addition, we have determined the structures of two NS5B polymerase/non-nucleoside inhibitor complexes. Both inhibitors bind at a common binding site, which is nearly 35 A away from the polymerase active site and is located in the thumb domain. The binding pocket is predominantly hydrophobic in nature, and the enzyme inhibitor complexes are stabilized by hydrogen bonding and van der Waals interactions. Inhibitors can only be soaked in crystal form I and not in form II; examination of the enzyme-inhibitor complex reveals that the enzyme has undergone a dramatic conformational change from the form I (active) complex to the form II (inactive).


Asunto(s)
Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , Modelos Moleculares , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/química , Secuencia de Aminoácidos , Sitios de Unión , Cristalización , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Genotipo , Hepacivirus/genética , Datos de Secuencia Molecular , Conformación Proteica , ARN Polimerasa Dependiente del ARN/metabolismo , Homología de Secuencia de Aminoácido , Tiofenos/química , Tiofenos/farmacología , Proteínas no Estructurales Virales/metabolismo
10.
Bioorg Med Chem Lett ; 15(6): 1693-5, 2005 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-15745823

RESUMEN

A novel class of macrocyclic 1,6-napthyridines designed to adopt the presumed bioactive conformation of anti-HCMV acyclic 1,6-napthyridines are described. Both 14- and 15-membered macrocycles were shown to be highly potent against HCMV HSV-1 and HSV-2.


Asunto(s)
Antivirales/química , Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Naftiridinas/química , Naftiridinas/farmacología , Antivirales/síntesis química , Diseño de Fármacos , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 2/efectos de los fármacos , Humanos , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Naftiridinas/síntesis química
11.
Bioorg Med Chem Lett ; 14(21): 5333-7, 2004 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-15454222

RESUMEN

HCV NS5B RNA-dependent RNA polymerase (NS5B) is essential for viral replication and is therefore considered a target for antiviral drug development. From our ongoing screening effort in the search for new anti-HCV agents, a novel inhibitor 1 with low microM activity against the HCV NS5B polymerase was identified. SAR analysis indicated the optimal substitution pattern required for activity, for example, carboxylic acid group at 2-position of thiophene ring. We describe the steps taken to identify and solve the bioactive conformation of derivative 6 through the use of the transferred NOE method (trNOE).


Asunto(s)
Antivirales/síntesis química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Sulfonamidas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Piridinas/química , ARN Polimerasa Dependiente del ARN/química , Relación Estructura-Actividad , Sulfonamidas/química , Tiofenos/química , Proteínas no Estructurales Virales/química
12.
Bioorg Med Chem Lett ; 14(3): 793-6, 2004 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-14741291
13.
Bioorg Med Chem Lett ; 14(3): 797-800, 2004 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-14741292

RESUMEN

Further SAR studies on the thiophene-2-carboxylic acids are reported. These studies led to the identification of a series of tertiary amides that show inhibition of both HCV NS5B polymerase in vitro and HCV subgenomic RNA replication in Huh-7 cells. Structural insights about the bioactive conformation of this class of molecules were deduced from a combination of modeling and transferred NOE (trNOE) studies.


Asunto(s)
Amidas/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , ARN Viral/metabolismo , Tiofenos/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Amidas/química , Ácidos Carboxílicos , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/virología , Inhibidores Enzimáticos/química , Genoma Viral , Humanos , Neoplasias Hepáticas/química , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/virología , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Replicón/efectos de los fármacos , Relación Estructura-Actividad , Tiofenos/química , Replicación Viral/efectos de los fármacos
16.
Vascul Pharmacol ; 40(2): 77-89, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12646396

RESUMEN

Integrin-mediated cell adhesion is necessary for endothelial cell proliferation and apoptosis, which is a major determinant in tumor-induced angiogenesis. In this study, we compared two novel, structurally similar, Arg-Gly-Asp (RGD) peptidomimetic compounds having different integrin selectivities, for their inhibition of endothelial cell proliferation and induction of apoptosis on functionally relevant extracellular matrices (ECM) for angiogenesis. BCH-14661 was specific for integrin alphavbeta3, whereas BCH-15046 nonselectively antagonized integrins alphavbeta3, alphavbeta5, and alpha5beta1. Both compounds were potent inducers of endothelial cell apoptosis when plated on RGD-dependent ECM (vitronectin, VN), which was dependent on the ability to induce cell detachment. However, with endothelial cells plated on RGD-independent ECM (type I collagen, COL), only BCH-15046 was able to significantly prevent growth and induce apoptosis. This effect was not dependent on the induction of detachment. Experiments using the matrix metalloproteinase (MMP) inhibitor GM 6001 revealed that cleavage of COL was not required for the ability of BCH-15046 to induce apoptosis. However, the inhibition of growth factor-stimulated endothelial cell proliferation, required MMPs, and correlated with BCH-15046s' potent inhibition of endothelial cell attachment to denatured collagen. Antibody inhibition experiments showed that adhesion to denatured collagen required integrins alphavbeta3 and beta1, but not alphavbeta5. In addition, BCH-15046 exerted a significant inhibition of VEGF-stimulated angiogenesis in the chick chorioallontoic membrane in vivo. These results suggest that integrin antagonism of both alphavbeta3 and alpha5beta1 are important for MMP-independent induction of apoptosis on COL and MMP-dependent inhibition of endothelial cell-denatured collagen interactions required for proliferation.


Asunto(s)
Apoptosis , Colágeno Tipo I/metabolismo , Endotelio Vascular/efectos de los fármacos , Guanidinas/farmacología , Integrina alfa5beta1/antagonistas & inhibidores , Integrina alfaVbeta3/antagonistas & inhibidores , Oligopéptidos/química , Sulfonamidas/farmacología , Anoicis , Adhesión Celular , División Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Endotelio Vascular/citología , Matriz Extracelular/fisiología , Guanidinas/química , Humanos , Integrina alfa5beta1/fisiología , Integrina alfaVbeta3/fisiología , Péptidos y Proteínas de Señalización Intercelular , Imitación Molecular , Neovascularización Patológica/patología , Péptidos/farmacología , Receptores Inmunológicos , Sulfonamidas/química , Vitronectina/metabolismo
17.
Bioorg Med Chem Lett ; 13(3): 503-6, 2003 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-12565960
18.
J Biol Chem ; 278(11): 9489-95, 2003 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-12509436

RESUMEN

X-ray crystal structures of two non-nucleoside analogue inhibitors bound to hepatitis C virus NS5B RNA-dependent RNA polymerase have been determined to 2.0 and 2.9 A resolution. These noncompetitive inhibitors bind to the same site on the protein, approximately 35 A from the active site. The common features of binding include a large hydrophobic region and two hydrogen bonds between both oxygen atoms of a carboxylate group on the inhibitor and two main chain amide nitrogen atoms of Ser(476) and Tyr(477) on NS5B. The inhibitor-binding site lies at the base of the thumb domain, near its interface with the C-terminal extension of NS5B. The location of this inhibitor-binding site suggests that the binding of these inhibitors interferes with a conformational change essential for the activity of the polymerase.


Asunto(s)
Nucleósidos/química , Proteínas no Estructurales Virales/genética , Sitio Alostérico , Secuencia de Aminoácidos , Sitios de Unión , Unión Competitiva , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Datos de Secuencia Molecular , Nitrógeno , Oxígeno , Unión Proteica , Conformación Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Serina/química , Tirosina/química
19.
Bioorg Med Chem Lett ; 12(21): 3063-6, 2002 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-12372502

RESUMEN

We have identified several nucleotide phosphonates demonstrating in vitro antiproliferative activity in several human cancer cell lines with IC(50) values in the microM range. The synthesis as well as structure-activity relationship are described.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Furanos/síntesis química , Furanos/farmacología , Nucleótidos/síntesis química , Nucleótidos/farmacología , Organofosfonatos/síntesis química , Organofosfonatos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Relación Estructura-Actividad , Timidina/metabolismo , Células Tumorales Cultivadas
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