RESUMO
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
Optimization of a high-throughput screening hit against melanin-concentrating hormone receptor 1 (MCHr1) led to the discovery of 2-(4-benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide (7a). This compound was found to be a high-affinity ligand for MCHr1 and a potent inhibitor of MCH-mediated Ca(2+) release, showed good plasma and CNS exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHr1 antagonist that is efficacious upon oral dosing in a chronic model of weight loss.
Assuntos
Acetamidas/síntese química , Fármacos Antiobesidade/síntese química , Indazóis/síntese química , Obesidade/tratamento farmacológico , Pirrolidinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Acetamidas/farmacocinética , Acetamidas/farmacologia , Administração Oral , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Ligação Competitiva , Encéfalo/metabolismo , Cálcio/metabolismo , Doença Crônica , Indazóis/farmacocinética , Indazóis/farmacologia , Camundongos , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ensaio Radioligante , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
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
Benzothiadiazine inhibitors of the HCV NS5B RNA-dependent RNA polymerase are an important class of non-nucleoside inhibitors that have received considerable attention in the search for novel HCV therapeutics. Research in our laboratories has identified a novel series of tetracyclic benzothiadiazine inhibitors of HCV polymerase bearing a benzylamino substituent on the B-ring. Compounds in this series exhibit low-nanomolar activities in both genotypes 1a and 1b polymerase inhibition assays and subgenomic replicon assays. Optimization of pharmacokinetic properties in rat led to compound 30, which has good oral bioavailability (F = 56%) and a favorable tissue distribution drug profile, with high liver to plasma ratios. Compound 30 is a potent inhibitor in replicon assays, with EC(50) values of 10 and 6 nM against genotypes 1a and 1b, respectively.
Assuntos
Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacologia , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Antivirais/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Benzotiadiazinas/farmacocinética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Genótipo , Hepacivirus/genética , Fígado/metabolismo , Testes de Sensibilidade Microbiana , Ratos , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
Assuntos
Antivirais/farmacocinética , Benzotiadiazinas/farmacocinética , Óxidos S-Cíclicos/farmacocinética , Inibidores Enzimáticos/farmacocinética , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/uso terapêutico , Benzotiadiazinas/química , Benzotiadiazinas/uso terapêutico , Disponibilidade Biológica , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/uso terapêutico , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Genótipo , Haplorrinos , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/sangue , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Estrutura Molecular , Pan troglodytes , Fenótipo , RNA Viral/sangue , RNA Polimerase Dependente de RNA/genética , Ratos , Carga Viral , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/genéticaRESUMO
A series of potent 2-carboxychromone-based melanin-concentrating hormone receptor 1 (MCHr1) antagonists were synthesized and evaluated for hERG (human Ether-a-go-go Related Gene) channel affinity and functional blockade. Basic dialkylamine-terminated analogs were found to weakly bind the hERG channel and provided marked improvement in a functional patch-clamp assay versus previously reported antagonists of the series.
Assuntos
Amidas/farmacologia , Cromonas/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Obesidade/tratamento farmacológico , Técnicas de Patch-Clamp , FarmacocinéticaRESUMO
The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.
Assuntos
Cromonas/síntese química , Cromonas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Depressores do Apetite/farmacologia , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Dieta , Gorduras na Dieta , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Fenfluramina/farmacologia , Indicadores e Reagentes , Camundongos , Conformação Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of urea-based N-1-(2-aminoethyl)-indazoles was synthesized and evaluated for melanin-concentrating hormone receptor 1 (MCHr1) antagonism in both binding and functional assays. Several compounds that acted as MCHr1 antagonists were identified, and optimization afforded a compound with excellent binding affinity, good functional potency, and oral efficacy in a chronic model for weight loss in diet-induced obese mice.
Assuntos
Indazóis/síntese química , Indazóis/farmacologia , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Ureia/química , Animais , Indazóis/química , Indazóis/uso terapêutico , Camundongos , Relação Estrutura-AtividadeRESUMO
The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.
Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Indazóis/síntese química , Indazóis/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Humanos , Indazóis/administração & dosagem , Camundongos , Piperidinas/química , Distribuição TecidualRESUMO
The identification of a novel series of benzamide-containing MCHr1 antagonists is described. Compound 22 displayed moderate efficacy in a diet induced obesity mice model.
Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/síntese química , Benzamidas/síntese química , Ligação Competitiva , Modelos Animais de Doenças , Cães , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Several potent and efficacious MCHr1 antagonists containing an ortho-amino benzamide or nicotinamide chemotype have been identified, exemplified by 28 and 50.
Assuntos
Niacinamida/análogos & derivados , Receptores de Somatostatina/antagonistas & inibidores , ortoaminobenzoatos/síntese química , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos , Niacinamida/farmacocinética , Niacinamida/farmacologia , Farmacocinética , Receptores de Somatostatina/agonistas , Relação Estrutura-Atividade , Distribuição Tecidual , ortoaminobenzoatos/farmacocinética , ortoaminobenzoatos/farmacologiaRESUMO
A high-throughput screen was performed in order to identify chemotypes that are bound by the melanin concentrating hormone receptor-1 (MCHr1). A novel 2-amino-8-alkoxyquinoline compound (1) was identified and subsequently optimized using a parallel and automated procedure for the rapid production of multiple analogs. The structure-activity relationships that emerged from this effort are described, along with selected pharmacokinetic parameters of compound (d)-61 when dosed orally in diet-induced obese mice.
Assuntos
Fármacos Antiobesidade/síntese química , Quinolinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Camundongos , Quinolinas/metabolismo , Quinolinas/farmacologia , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
The continued SAR investigation of 2-amino-8-alkoxy quinolines as melanin concentrating hormone receptor-1 (MCHr1) antagonists is reported. Prior hit-to-lead efforts resulted in the identification of 1 as a robust MCHr1 antagonist. Further delineation of the structural parameters essential for MCHr1-binding affinity of this class of nontraditional GPCR ligands resulted in the identification of compounds such as 33, 34 and 37, which demonstrate single digit nanomolar antagonism of MCHr1-mediated Ca(2+) release. The synthesis and biological evaluation of these compounds are reported.
Assuntos
Fármacos Antiobesidade/síntese química , Quinolinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Camundongos , Quinolinas/metabolismo , Quinolinas/farmacologia , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
Prior SAR studies on 2-amino-8-alkoxyquinoline MCHr1 antagonists demonstrated that compounds with acyclic amide-containing sidechains displayed exceptional binding and functional potency, but negligible CNS penetration. Related analogs with acyclic benzylamine-containing sidechains showed greatly improved CNS exposure, but suffered in functional potency. In this report, we demonstrate that cyclization of these benzylic amine sidechains affords compounds that combine the best elements of potency and CNS penetration among this class of antagonists. This is exemplified by compound 21, which has sub-nanomolar MCHr1 binding affinity, good functional potency, and excellent CNS exposure over 24h.