RESUMO
The HBV capsid core protein serves a number of important functions in the viral life cycle enabling chronic HBV infection to persist, and therefore is a promising drug target. Interfering with capsid assembly has shown efficacy in clinical trials with small molecule capsid assembly modulators (CAMs). Herein is described the further optimization of a progressive series of diazepinone HBV CAMs.
Assuntos
Capsídeo , Vírus da Hepatite B , Antivirais/metabolismo , Capsídeo/metabolismo , Proteínas do Capsídeo/metabolismo , Vírus da Hepatite B/metabolismo , Montagem de VírusRESUMO
The HBV core protein serves multiple essential functions in the viral life cycle that enable chronic HBV infection to persist, and as such, represents a promising drug target. Modulation of the HBV capsid assembly has shown efficacy in early clinical trials through use of small molecule capsid assembly modulators (CAMs). Herein is described the evolution and SAR of a novel pyrazolo piperidine lead series into advanced oxadiazepinone HBV CAMs.
Assuntos
Antivirais/farmacologia , Azepinas/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Vírus da Hepatite B/efeitos dos fármacos , Antivirais/química , Azepinas/química , Proteínas do Capsídeo/metabolismo , Relação Dose-Resposta a Droga , Vírus da Hepatite B/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The HBV core protein is a druggable target of interest due to the multiple essential functions in the HBV life cycle to enable chronic HBV infection. The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly has shown efficacy in clinical trials. Herein is described the identification and hit to lead SAR of a novel series of pyrazolo piperidine HBV capsid assembly modulators.
Assuntos
Antivirais/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Vírus da Hepatite B/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Antivirais/química , Proteínas do Capsídeo/metabolismo , Relação Dose-Resposta a Droga , Vírus da Hepatite B/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/química , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
NVR 3-778 is the first capsid assembly modulator (CAM) that has demonstrated antiviral activity in hepatitis B virus (HBV)-infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA-containing virus particles with a mean antiviral 50% effective concentration (EC50) of 0.40 µM in HepG2.2.15 cells. The antiviral profile of NVR 3-778 indicates pan-genotypic antiviral activity and a lack of cross-resistance with nucleos(t)ide inhibitors of HBV replication. The combination of NVR 3-778 with nucleos(t)ide analogs in vitro resulted in additive or synergistic antiviral activity. Mutations within the hydrophobic pocket at the dimer-dimer interface of the core protein could confer resistance to NVR 3-778, which is consistent with the ability of the compound to bind to core and to induce capsid assembly. By targeting core, NVR 3-778 inhibits pregenomic RNA encapsidation, viral replication, and the production of HBV DNA- and HBV RNA-containing particles. NVR 3-778 also inhibited de novo infection and viral replication in primary human hepatocytes with EC50 values of 0.81 µM against HBV DNA and between 3.7 and 4.8 µM against the production of HBV antigens and intracellular HBV RNA. NVR 3-778 showed favorable pharmacokinetics and safety in animal species, allowing serum levels in excess of 100 µM to be achieved in mice and, thus, enabling efficacy studies in vivo The overall preclinical profile of NVR 3-778 predicts antiviral activity in vivo and supports its further evaluation for safety, pharmacokinetics, and antiviral activity in HBV-infected patients.
Assuntos
Antivirais/farmacologia , Benzamidas/farmacologia , Capsídeo/efeitos dos fármacos , DNA Viral/antagonistas & inibidores , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Piperidinas/farmacologia , RNA Viral/antagonistas & inibidores , Animais , Antígenos Virais/genética , Antígenos Virais/metabolismo , Antivirais/sangue , Antivirais/química , Antivirais/farmacocinética , Benzamidas/sangue , Benzamidas/química , Benzamidas/farmacocinética , Capsídeo/química , Capsídeo/metabolismo , DNA Viral/genética , DNA Viral/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Células Hep G2 , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Piperidinas/sangue , Piperidinas/química , Piperidinas/farmacocinética , Cultura Primária de Células , RNA Viral/genética , RNA Viral/metabolismo , Proteínas do Core Viral/antagonistas & inibidores , Proteínas do Core Viral/genética , Proteínas do Core Viral/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
The HBV core protein has multiple essential functions in the HBV life cycle to enable chronic HBV infection. The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly process has shown clinical efficacy in early clinical trials. Herein is described the SAR exploration of NVR 3-778, the first clinical compound in the sulfonyl carboxamide class.
Assuntos
Antivirais/farmacologia , Benzamidas/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Vírus da Hepatite B/efeitos dos fármacos , Piperidinas/farmacologia , Antivirais/síntese química , Antivirais/química , Benzamidas/síntese química , Benzamidas/química , Proteínas do Capsídeo/metabolismo , Relação Dose-Resposta a Droga , Vírus da Hepatite B/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Montagem de Vírus/efeitos dos fármacosRESUMO
The hepatitis B virus (HBV) core protein serves multiple essential functions in the viral life cycle, and antiviral agents that target the core protein are being developed. Capsid assembly modulators (CAMs) are compounds that target core and misdirect capsid assembly, resulting in the suppression of HBV replication and virion production. Besides HBV DNA, circulating HBV RNA has been detected in patient serum and can be associated with the treatment response. Here we studied the effect of HBV CAMs on the production of extracellular HBV RNA using infected HepaRG cells and primary human hepatocytes. Representative compounds from the sulfonamide carboxamide and heteroaryldihydropyrimidine series of CAMs were evaluated and compared to nucleos(t)ide analogs as inhibitors of the viral polymerase. The results showed that CAMs blocked extracellular HBV RNA with efficiencies similar to those with which they blocked pregenomic RNA (pgRNA) encapsidation, HBV DNA replication, and Dane particle production. Nucleos(t)ide analogs inhibited viral replication and virion production but not encapsidation or production of extracellular HBV RNA. Profiling of HBV RNA from both culture supernatants and patient serum showed that extracellular viral RNA consisted of pgRNA and spliced pgRNA variants with an internal deletion(s) but still retained the sequences at both the 5' and 3' ends. Similar variants were detected in the supernatants of infected cells with and without nucleos(t)ide analog treatment. Overall, our data demonstrate that HBV CAMs represent direct antiviral agents with a profile differentiated from that of nucleos(t)ide analogs, including the inhibition of extracellular pgRNA and spliced pgRNA.
Assuntos
Antivirais/farmacologia , Proteínas do Capsídeo/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Proteínas do Nucleocapsídeo/metabolismo , Montagem de Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Linhagem Celular , DNA Viral/sangue , DNA Polimerase Dirigida por DNA/metabolismo , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatócitos/virologia , Humanos , Inibidores da Síntese de Ácido Nucleico/farmacologia , RNA Viral/sangue , Sulfonamidas/farmacologia , Proteínas do Core Viral/metabolismoRESUMO
Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, IKur, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current IKs, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for IKur over IKs (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans.
Assuntos
Canal de Potássio Kv1.5/antagonistas & inibidores , Piridinas/farmacologia , Descoberta de Drogas , Humanos , Piridinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
A new series of CB2-selective agonists containing a benzimidazole core is reported. Design, synthesis, SAR and pharmacokinetic data for selected compounds are described.
Assuntos
Benzimidazóis/farmacologia , Desenho de Fármacos , Receptor CB2 de Canabinoide/agonistas , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.
Assuntos
Amidas/química , Naftalenos/química , Quinolizidinas/química , Receptor Muscarínico M1/metabolismo , Regulação Alostérica , Amidas/síntese química , Amidas/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Camundongos , Ligação Proteica , Receptor Muscarínico M1/química , Relação Estrutura-AtividadeRESUMO
Elevated plasma homocysteine (Hcy) levels are an independent risk factor for the onset and progression of Alzheimer's disease. Reduction of Hcy to normal levels therefore presents a new approach for disease modification. Hcy is produced by the cytosolic enzyme S-adenosylhomocysteine hydrolase (AHCY), which converts S-adenosylhomocysteine (SAH) to Hcy and adenosine. Herein we describe the design and characterization of novel, substrate-based S-adenosylhomocysteine hydrolase inhibitors with low nanomolar potency in vitro and robust activity in vivo.
Assuntos
Adenosina/análogos & derivados , Desenho de Fármacos , Hidrolases/antagonistas & inibidores , S-Adenosil-Homocisteína , Adenosina/química , Adenosina/farmacologia , Animais , Química Encefálica , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Homocisteína/sangue , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Moleculares , Ratos , S-Adenosil-Homocisteína/química , Especificidade por SubstratoRESUMO
Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.
Assuntos
Descoberta de Drogas , Antagonistas dos Receptores de Orexina , Piridinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Tiazóis/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
Assuntos
Ácidos Nicotínicos/química , Ácidos Nicotínicos/farmacologia , Antagonistas dos Receptores de Orexina , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Receptores de Orexina/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.
Assuntos
Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/química , Piridinas/síntese química , Tiazóis/síntese química , Amidas/química , Antineoplásicos/farmacologia , Sítios de Ligação , Quinase 1 do Ponto de Checagem , Cristalografia por Raios X , Desenho de Fármacos , Etilenodiaminas/química , Humanos , Ligação de Hidrogênio , Cinética , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Piridinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/farmacologia , Água/químicaRESUMO
Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series.
Assuntos
Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/química , Piridinas/síntese química , Tiazóis/síntese química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Quinase 1 do Ponto de Checagem , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/química , Desenho de Fármacos , Halogenação , Humanos , Cinética , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Piridinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/farmacologia , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.
Assuntos
Androgênios/metabolismo , Azasteroides/farmacologia , Antagonistas de Hormônios/farmacologia , Receptores Androgênicos/química , Transcrição Gênica , Animais , Azasteroides/química , Células COS , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Chlorocebus aethiops , Desenho de Fármacos , Feminino , Humanos , Ligantes , Masculino , Modelos Biológicos , Estrutura Terciária de Proteína , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Esteroides/metabolismo , Ativação TranscricionalRESUMO
Fused aromatics such as naphthalene were identified as highly potent and CNS penetrant M(1) positive allosteric modulators during an SAR study to replace the phenyl B-ring linkage.
Assuntos
Naftóis/química , Receptor Muscarínico M1/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/líquido cefalorraquidiano , Regulação Alostérica/efeitos dos fármacos , Animais , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Humanos , Estrutura Molecular , Naftóis/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.
Assuntos
Piperidinas/farmacologia , Regulação Alostérica , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Piperidinas/metabolismo , Relação Estrutura-AtividadeRESUMO
The Merck Fragment Library was screened versus acid-sensing ion channel 3 (ASIC3), a novel target for the treatment of pain. Fragment hits were optimized using two strategies, and potency was improved from 0.7 mM to 3 µM with retention of good ligand efficiency and incorporation of reasonable physical properties, off-target profile, and rat pharmacokinetics.
Assuntos
Descoberta de Drogas , Fenômenos Eletrofisiológicos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Canais Iônicos Sensíveis a Ácido , Animais , Estrutura Molecular , Fragmentos de Peptídeos , Ratos , Bibliotecas de Moléculas Pequenas , Canais de SódioRESUMO
A novel series of decahydroquinoline CB2 agonists is described. Optimization of the amide substituent led to improvements in CB2/CB1 selectivity as well as physical properties. Two key compounds were examined in the rat CFA model of acute inflammatory pain. A moderately selective CB2 agonist was active in this model. A CB2 agonist lacking functional CB1 activity was inactive in this model despite high in vivo exposure both peripherally and centrally.
Assuntos
Amidas/química , Analgésicos/química , Quinolinas/química , Receptor CB2 de Canabinoide/agonistas , Amidas/síntese química , Amidas/uso terapêutico , Analgésicos/síntese química , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Dor/tratamento farmacológico , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition.