RESUMO
Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.
Assuntos
Produtos Biológicos/síntese química , Desenho de Fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Oral , Regulação Alostérica , Animais , Artrite Reumatoide/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Ligantes , Camundongos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1-6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1-6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1-6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors.
Assuntos
Antivirais/química , Antivirais/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Pirrolidinas/química , Pirrolidinas/farmacologia , Animais , Antivirais/farmacocinética , Benzimidazóis/farmacocinética , Genótipo , Hepacivirus/genética , Hepacivirus/fisiologia , Camundongos , Pirrolidinas/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual , Replicação Viral/efeitos dos fármacosRESUMO
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
Assuntos
Citosina/análogos & derivados , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Estilbenos/química , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Técnicas de Química Sintética , Citosina/síntese química , Citosina/química , Citosina/farmacocinética , Citosina/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Permeabilidade , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacocinética , Distribuição Tecidual , Proteínas não Estruturais Virais/químicaRESUMO
We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.
Assuntos
Anilidas/farmacologia , Antivirais/farmacologia , Carbamatos/farmacologia , Genótipo , Hepacivirus/efeitos dos fármacos , Sulfonamidas/farmacologia , Uracila/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , 2-Naftilamina , Anilidas/química , Anilidas/farmacocinética , Animais , Antivirais/química , Antivirais/farmacocinética , Disponibilidade Biológica , Carbamatos/química , Carbamatos/farmacocinética , Linhagem Celular , Descoberta de Drogas , Hepacivirus/enzimologia , Humanos , Prolina , Ratos , Sulfonamidas/química , Sulfonamidas/farmacocinética , Uracila/química , Uracila/farmacocinética , Uracila/farmacologia , ValinaRESUMO
The synthesis and structure-activity relationships of a novel aryl uracil series which contains a fused 5,6-bicyclic ring unit for HCV NS5B inhibition is described. Several analogs display replicon cell culture potencies in the low nanomolar range along with excellent rat pharmacokinetic values.
Assuntos
Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Uracila/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacocinética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , Ratos , Relação Estrutura-Atividade , Uracila/farmacologia , Proteínas não Estruturais Virais/metabolismoRESUMO
The synthesis of several pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine analogs is described with one such analog possessing subnanomolar potency in both genotype 1a and 1b cell culture HCV replicon assays.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Pirimidinas/síntese química , RNA Viral/antagonistas & inibidores , Antivirais/farmacologia , Linhagem Celular Tumoral , Genótipo , Hepacivirus/fisiologia , Humanos , Pirimidinas/farmacologia , RNA Viral/biossíntese , Replicon/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.
Assuntos
Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Animais , Benzotiadiazinas/farmacocinética , Disponibilidade Biológica , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Humanos , Espectroscopia de Ressonância Magnética , Ratos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The synthesis of several pyrrolidine inhibitor analogs is described that possess nanomolar in vitro potencies against the neuraminidase enzymes expressed by the B/Memphis/3/89 and A/N1/PR/8/34 influenza strains.
Assuntos
Antivirais/química , Antivirais/farmacologia , Neuraminidase/antagonistas & inibidores , Pirrolidinas/química , Pirrolidinas/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Substituted 1-hydroxy-4,4-dialkyl-3-oxo-3,4-dihydronaphthalene benzothiadiazine derivatives were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed. It was found that the saturated alkane dialkyl units provided the most active analogs.
Assuntos
Antivirais/síntese química , Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacologia , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Alcanos , Antivirais/farmacologia , Hepacivirus/enzimologia , Concentração Inibidora 50 , Replicon/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Substituted N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed.