RESUMO
Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non-fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series.
Assuntos
Antivirais/química , Antivirais/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Benzimidazóis/farmacocinética , Cães , Genótipo , Halogenação , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatite C/tratamento farmacológico , Humanos , Camundongos , Ratos , Replicon/efeitos dos fármacos , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismoRESUMO
A series of structurally novel stearoyl-CoA desaturase1 (SCD1) inhibitors has been identified via molecular scaffold manipulation. Preliminary structure-activity relationship (SAR) studies led to the discovery of potent, and orally bioavailable piperidine-aryl urea-based SCD1 inhibitors. 4-(2-Chlorophenoxy)-N-[3-(methyl carbamoyl)phenyl]piperidine-1-carboxamide 4c exhibited robust in vivo activity with dose-dependent desaturation index lowering effects.
Assuntos
Inibidores Enzimáticos/farmacologia , Piperidinas/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Especificidade por Substrato , Ureia/químicaRESUMO
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
Ghrelin, a gut-derived orexigenic hormone, is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). Centrally administered ghrelin has been shown to cause hunger and increase food intake in rodents. Inhibition of ghrelin actions with ghrelin antibody, peptidyl GHS-R antagonists, and antisense oligonucleosides resulted in weight loss and food intake decrease in rodents. Here we report the effects of GHS-R antagonists, some of which were potent, selective, and orally bioavailable. A structure-activity relationship study led to the discovery of 8a, which was effective in decreasing food intake and body weight in several acute rat studies.
Assuntos
Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptores de Grelina , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases.
Assuntos
Aminopiridinas/síntese química , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Aminopiridinas/química , Aminopiridinas/farmacologia , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Meia-Vida , Humanos , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/química , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Fosforilação , Conformação Proteica , Ratos , Ratos Sprague-DawleyRESUMO
C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of inhibiting these enzymes and as leads for potential drugs targeting JNKs. In this report, we disclose a series of potent and highly selective JNK inhibitors with good pharmacokinetic profiles.
Assuntos
Amidas/síntese química , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Piridinas/síntese química , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , TermodinâmicaRESUMO
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 the 4- and 6-substituents of 2,4-diaminopyrimidine-based growth hormone secretagogue receptor (GHS-R) antagonists are described. Diaminopyrimidines with 6-norbornenyl (4n) and 6-tetrahydrofuranyl (4p) substitutents were found to exhibit potent GHS-R antagonism and good selectivity (approximately 1000-fold) against dihydrofolate reductase.
Assuntos
Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Pirimidinas/química , Receptores de Grelina , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/efeitos dos fármacosRESUMO
The structure-activity relationship studies on a series of tetralin carboxamide growth hormone secretagogue receptor (GHS-R) antagonists are discussed. It was found that certain 2-alkoxycarbonylamino substituted tetralin carboxamides are potent, selective, and orally bioavailable GHS-R antagonists.
Assuntos
Amidas/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Tetra-Hidronaftalenos/farmacologia , Administração Oral , Amidas/farmacologia , Animais , Sítios de Ligação , Disponibilidade Biológica , Desenho de Fármacos , Concentração Inibidora 50 , Fenilenodiaminas/química , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Grelina , Relação Estrutura-AtividadeRESUMO
Farnesyltransferase inhibitors (FTIs) have been developed as potential anti-cancer agents due to their efficacy in blocking malignant growth in a variety of murine models of human tumors. To that end, we have developed a series of pyridone farnesyltransferase inhibitors with potent in vitro and cellular activity. The synthesis, SAR and biological properties of these compounds will be discussed.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/síntese química , Piridonas/síntese química , Piridonas/farmacologia , Animais , Antineoplásicos/toxicidade , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/toxicidade , Farnesiltranstransferase , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered a series of aryl tetrahydropyridines that incorporate substituted glycine, phenylalanine and histidine residues. The design, synthesis, SAR and biological properties of these compounds will be discussed.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicina/análogos & derivados , Histidina/análogos & derivados , Fenilalanina/análogos & derivados , Piridinas/síntese química , Piridinas/farmacologia , Disponibilidade Biológica , Cristalografia por Raios X , Inibidores Enzimáticos/farmacocinética , Farnesiltranstransferase , Genes ras/efeitos dos fármacos , Glicina/farmacologia , Histidina/farmacologia , Modelos Moleculares , Conformação Molecular , Fenilalanina/farmacologia , Relação Estrutura-AtividadeRESUMO
Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered bioavailable aryl tetrahydropyridines that are potent in cell culture. The design, synthesis, SAR and biological properties of these compounds will be discussed.