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1.
Bioorg Med Chem Lett ; 27(15): 3294-3300, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28633899

RESUMO

The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM.


Assuntos
Antivirais/química , Antivirais/farmacologia , Benzazepinas/química , Benzazepinas/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Benzazepinas/farmacocinética , Cães , Haplorrinos , Hepacivirus/enzimologia , Hepacivirus/metabolismo , Hepatite C/virologia , Humanos , RNA Replicase/antagonistas & inibidores , RNA Replicase/metabolismo , Ratos , Proteínas não Estruturais Virais/metabolismo
2.
3.
J Biol Chem ; 289(48): 33456-68, 2014 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-25301950

RESUMO

HCV infection is an urgent global health problem that has triggered a drive to discover therapies that specifically target the virus. BMS-791325 is a novel direct antiviral agent specifically targeting HCV NS5B, an RNA-dependent RNA polymerase. Robust viral clearance of HCV was observed in infected patients treated with BMS-791325 in combination with other anti-HCV agents in Phase 2 clinical studies. Biochemical and biophysical studies revealed that BMS-791325 is a time-dependent, non-competitive inhibitor of the polymerase. Binding studies with NS5B genetic variants (WT, L30S, and P495L) exposed a two-step, slow binding mechanism, but details of the binding mechanism differed for each of the polymerase variants. For the clinically relevant resistance variant (P495L), the rate of initial complex formation and dissociation is similar to WT, but the kinetics of the second step is significantly faster, showing that this variant impacts the final tight complex. The resulting shortened residence time translates into the observed decrease in inhibitor potency. The L30S variant has a significantly different profile. The rate of initial complex formation and dissociation is 7-10 times faster for the L30S variant compared with WT; however, the forward and reverse rates to form the final complex are not significantly different. The impact of the L30S variant on the inhibition profile and binding kinetics of BMS-791325 provides experimental evidence for the dynamic interaction of fingers and thumb domains in an environment that supports the formation of active replication complexes and the initiation of RNA synthesis.


Assuntos
Antivirais/química , Benzazepinas/química , Hepacivirus/enzimologia , Indóis/química , RNA Replicase/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Substituição de Aminoácidos , Antivirais/farmacologia , Benzazepinas/uso terapêutico , Hepatite C/tratamento farmacológico , Hepatite C/enzimologia , Humanos , Indóis/uso terapêutico , Mutação de Sentido Incorreto , Ligação Proteica , RNA Replicase/química , RNA Replicase/metabolismo , RNA Viral/biossíntese , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
4.
Antimicrob Agents Chemother ; 58(6): 3485-95, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24733465

RESUMO

BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC50) below 28 nM. In cell culture, BMS-791325 inhibited replication of HCV subgenomic replicons representing genotypes 1a and 1b at 50% effective concentrations (EC50s) of 3 nM and 6 nM, respectively, with similar (3 to 18 nM) values for genotypes 3a, 4a, and 5a. Potency against genotype 6a showed more variability (9 to 125 nM), and activity was weaker against genotype 2 (EC50, 87 to 925 nM). Specificity was demonstrated by the absence of activity (EC50s of >4 µM) against a panel of mammalian viruses, and cytotoxic concentrations (50%) were >3,000-fold above the HCV EC50. Resistance substitutions selected by BMS-791325 in genotype 1 replicons mostly mapped to a single site, NS5B amino acid 495 (P495A/S/L/T). Additive or synergistic activity was observed in combination studies using BMS-791325 with alfa interferon plus ribavirin, inhibitors of NS3 protease or NS5A, and other classes of NS5B inhibitor (palm site 2-binding or nucleoside analogs). Plasma and liver exposures in vivo in several animal species indicated that BMS-791325 has a hepatotropic disposition (liver-to-plasma ratios ranging from 1.6- to 60-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥ 10-fold above the inhibitor EC50s observed with HCV genotype 1 replicons. These findings support the evaluation of BMS-791325 in combination regimens for the treatment of HCV. Phase 3 studies are ongoing.


Assuntos
Antivirais/farmacologia , Benzazepinas/farmacologia , Hepacivirus/enzimologia , Indóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Animais , Antivirais/química , Benzazepinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cercopithecus aethiops , Cães , Farmacorresistência Viral , Quimioterapia Combinada , Genótipo , Hepacivirus/efeitos dos fármacos , Humanos , Indóis/química , Interferon-alfa/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , RNA Replicase/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Replicon/efeitos dos fármacos , Ribavirina/farmacologia , Células Vero
5.
Bioorg Med Chem Lett ; 22(8): 2866-71, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22424979

RESUMO

Presented here are initial structure-activity relationship (SAR) studies on a series of novel heteroaryl fused tetracyclic indole-based inhibitors of the hepatitis C viral polymerase, NS5B. The introduction of alternative heterocyclic moieties into the indolo-fused inhibitor class significantly expands the reported SAR and resulted in the identification of pyridino analogs, typified by compounds 44 and 45 that displayed excellent potency against the NS5B polymerase of both HCV 1a and HCV 1b genotypes.


Assuntos
Amidas/química , Hepacivirus/efeitos dos fármacos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Amidas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Indóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Relação Estrutura-Atividade
6.
Org Biomol Chem ; 9(19): 6654-62, 2011 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-21800000

RESUMO

Three synthetic approaches have been developed that allow efficient access to novel heteroaryl fused indole ring systems, including: 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indoles, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles and 1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles. Each strategy is fully exemplified and the relative merits and limitations of the approaches are discussed. The hepatitis C virus (HCV) non-structural 5B (NS5B) polymerase inhibitory activities of select examples from each molecular class are briefly presented.


Assuntos
Indóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Técnicas de Química Sintética , Indóis/síntese química , Indóis/química , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 21(10): 2925-9, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21486696

RESUMO

Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC(50)=0.07 µM, %F=18), are reported.


Assuntos
Ativação Enzimática/efeitos dos fármacos , Hepacivirus/enzimologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Indóis/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Desenho de Drogas , Compostos Heterocíclicos/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
8.
Arch Biochem Biophys ; 470(2): 146-52, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18062913

RESUMO

The enzymatic activity of hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B is modulated by the molar ratio of NS5B enzyme and RNA template. Depending on the ratio, either template or enzyme can inhibit activity. Inhibition of NS5B activity by RNA template exhibited characteristics of substrate inhibition, suggesting the template binds to a secondary site on the enzyme forming an inactive complex. Template inhibition was modulated by primer. Increasing concentrations of primer restored NS5B activity and decreased the affinity of template for the secondary site. Conversely, increasing template concentration reduced the affinity of primer binding. The kinetic profiles suggest template inhibition results from the binding of template to a site that interferes with primer binding and the formation of productive replication complexes.


Assuntos
RNA/química , RNA/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Sítios de Ligação , Ativação Enzimática , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Ligação Proteica
9.
Anal Biochem ; 359(1): 106-11, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17054898

RESUMO

Discovery and development of effective antiviral agents to combat hepatitis C virus (HCV) is the focus of intensive research both in academia and in pharmaceutical companies. One of the HCV nonstructural proteins, NS5B (an RNA-dependent RNA polymerase), represents an attractive target in light of the clinical success of human immunodeficiency virus reverse transcriptase inhibitors. To identify and evaluate NS5B inhibitors, we developed a homogeneous, solid-phase, high-throughput biochemical assay for detecting NS5B enzymatic activity. In this assay, a biotinylated oligo(dT(12)) primer was immobilized onto streptavidin-coated scintillation proximity assay (SPA) beads, and after addition of homopolymeric A template, NS5B enzyme, and radiolabeled uridine 5'-triphosphate, the primer-dependent RNA synthesis occurred on beads. Optimization of the on-bead reaction resulted in the use of significantly less RNA template and NS5B enzyme while producing a faster steady state reaction rate compared to the solution-phase or off-bead SPA. The newly developed solid-phase assay is functionally comparable to the solution-phase assay as similar potencies of HCV NS5B inhibitors tested were obtained with the two assays. Furthermore, the solid-phase assay offers the advantage of delaying initiation, mimicking a physical preincubation step required for evaluating time-dependent inhibitors.


Assuntos
Antivirais/farmacologia , Hepacivirus/enzimologia , RNA Replicase/antagonistas & inibidores , RNA Replicase/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Antivirais/química , Bioensaio , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Enzimas Imobilizadas , Hepacivirus/genética , Humanos , Concentração Inibidora 50 , RNA Replicase/análise , RNA Replicase/genética , RNA Viral/biossíntese , RNA Viral/genética , Moldes Genéticos , Proteínas não Estruturais Virais/análise , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos
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