RESUMO
As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). This manuscript reports the synthesis and structure-activity relationship (SAR) studies for a novel series of JNK inhibitors demonstrating an increased JNK1 bias. SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191).
Assuntos
Cicloexilaminas/farmacologia , Descoberta de Drogas , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Cicloexilaminas/uso terapêutico , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fosforilação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.
Assuntos
Cicloexanóis/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Proteína Quinase C-theta/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Cicloexanóis/síntese química , Cicloexanóis/metabolismo , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Proteína Quinase C-delta/antagonistas & inibidores , Proteína Quinase C-delta/metabolismo , Proteína Quinase C-theta/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacosRESUMO
TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (8: TTK IC50 = 3.0 nM; CAL-51 IC50 = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor 6 (TTK IC50 = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of 25 (TTK IC50 = 3.0 nM; CAL-51 IC50 = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Antineoplásicos , Neoplasias da Mama , Linhagem Celular Tumoral , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.
Assuntos
Acetamidas/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/uso terapêutico , Isoindóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores de Terminação de Peptídeos/antagonistas & inibidores , Piperidonas/uso terapêutico , Ubiquitina-Proteína Ligases/metabolismo , Acetamidas/química , Acetamidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Isoindóis/química , Isoindóis/farmacologia , Macaca fascicularis , Masculino , Camundongos , Estrutura Molecular , Fatores de Terminação de Peptídeos/química , Fatores de Terminação de Peptídeos/metabolismo , Piperidonas/química , Piperidonas/farmacologia , Proteólise/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
There is a growing interest in using targeted protein degradation as a therapeutic modality in view of its potential to expand the druggable proteome. One avenue to using this modality is via molecular glue based Cereblon E3 Ligase Modulating Drug compounds. Here, we report the identification of the transcription factor ZBTB16 as a Cereblon neosubstrate. We also report two new Cereblon modulators, CC-3060 and CC-647, that promote ZBTB16 degradation. Unexpectedly, CC-3060 and CC-647 target ZBTB16 for degradation by primarily engaging distinct structural degrons on different zinc finger domains. The reciprocal fusion proteins, ZBTB16-RARα and RARα-ZBTB16, which cause a rare acute promyelocytic leukemia, contain these same structural degrons and can be targeted for proteasomal degradation with Cereblon modulator treatment. Thus, a targeted protein degradation approach via Cereblon modulators may represent a novel therapeutic strategy in acute promyelocytic leukemia where ZBTB16/RARA rearrangements are critical disease drivers.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Humanos , Leucemia Promielocítica Aguda/metabolismo , Proteólise , Receptor alfa de Ácido Retinoico/metabolismo , Especificidade por SubstratoRESUMO
Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Mieloma Múltiplo/patologia , Recidiva , Estereoisomerismo , Falha de Tratamento , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Docetaxel/uso terapêutico , Desenho de Fármacos , Feminino , Camundongos SCID , Proteínas Associadas aos Microtúbulos/metabolismo , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure-activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3-CRBN-GSPT1 cocrystal ternary complex. For SAR that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos.
Assuntos
Fator de Transcrição Ikaros/metabolismo , Fatores de Terminação de Peptídeos/metabolismo , Proteólise/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Antineoplásicos/química , Antineoplásicos/farmacologia , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Fator de Transcrição Ikaros/química , Fator de Transcrição Ikaros/genética , Simulação de Acoplamento Molecular , Mieloma Múltiplo , Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , Fatores de Terminação de Peptídeos/química , Fatores de Terminação de Peptídeos/genética , Ftalimidas/química , Piperidonas/químicaRESUMO
The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis and relapsed/refractory multiple myeloma. Compound 6 binds cereblon with a higher affinity than lenalidomide or pomalidomide. Consistent with this, the cellular degradation of Ikaros and Aiolos is more potent and the extent of substrate depletion is greater. The crystal structure of cereblon in complex with DDB1 and compound 6 reveals that the increase in potency correlates with increased contacts between compound 6 and cereblon away from the modeled binding site for Ikaros/Aiolos. These results describe a new cereblon modulator which achieves greater substrate degradation via tighter binding to the cereblon E3 ligase and provides an example of the effect of E3 ligase binding affinity with relevance to other drug discovery efforts in targeted protein degradation.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fator de Transcrição Ikaros/metabolismo , Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , Proteólise/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal , Linhagem Celular Tumoral , Cristalografia por Raios X , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Transferência Ressonante de Energia de Fluorescência , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Lenalidomida/química , Lenalidomida/metabolismo , Morfolinas , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Ftalimidas , Piperidonas , Ligação Proteica , Ubiquitina-Proteína LigasesRESUMO
Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/síntese química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Camundongos , Mitose/efeitos dos fármacos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Splicing de RNA/efeitos dos fármacos , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/enzimologiaRESUMO
INTRODUCTION: HIV infection is often preceded or accompanied by psychiatric comorbidities. These disorders improve with complementary therapies. The aim of this study was to measure the effect of massage therapy on anxiety, depression, hyperventilation and quality of life in HIV infected patients. METHOD: Adult HIV-infected patients were randomized (n=29) in massage therapy group (one hour a week during four weeks) and control group. Anxiety and depression (HADS-A and HADS-D), hyperventilation (Nijmegen questionnaire) and quality of life (WHOQOL-HIV) were evaluated at inclusion and after 4 weeks. RESULTS: At inclusion, 51% and 17% of the patients had a positive HADS-A and HADS-D score respectively. Two facets from WHOQOL-HIV ("Home environment" and "Death and dying" (p=0.04)) were different between groups. After the four week massage therapy, a significant improvement was observed only for Nijmegen questionnaire (p=0.01) and HADS-A (p=0.04) contrarily to WHOQOL-HIV and HADS-D. Domains of the WHOQOL-HIV did not improve following the massage therapy. Only "Pain and discomfort" facet improved after massage therapy (p=0.04). CONCLUSION: This study highlights the positive impact of a four week massage therapy on anxiety and hyperventilation in HIV infected patients. However, neither benefit of this program was observed on depression and quality of life.
Assuntos
Ansiedade/terapia , Depressão/terapia , Infecções por HIV/complicações , Hiperventilação/terapia , Massagem , Qualidade de Vida , Adulto , Idoso , Ansiedade/etiologia , Depressão/etiologia , Humanos , Hiperventilação/etiologia , Pessoa de Meia-IdadeRESUMO
Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1α in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA.
Assuntos
Indazóis/química , Inflamação/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/química , Triazóis/química , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/fisiopatologia , Basófilos/citologia , Linhagem Celular , Colágeno/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Edema/patologia , Eosinófilos/citologia , Feminino , Células HEK293 , Humanos , Hipertensão/tratamento farmacológico , Inflamação/fisiopatologia , Concentração Inibidora 50 , Janus Quinase 2/antagonistas & inibidores , Masculino , Neutropenia/tratamento farmacológico , Neutrófilos/citologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Receptores Fc/química , Pele/patologia , Quinase Syk , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
In modern day drug discovery campaigns, computational chemists have to be concerned not only about improving the potency of molecules but also reducing any off-target ADMET activity. There are a plethora of antitargets that computational chemists may have to consider. Fortunately many antitargets have crystal structures deposited in the PDB. These structures are immediately useful to our Autocorrelator: an automated model generator that optimizes variables for building computational models. This paper describes the use of the Autocorrelator to construct high quality docking models for cytochrome P450 2C9 (CYP2C9) from two publicly available crystal structures. Both models result in strong correlation coefficients (R² > 0.66) between the predicted and experimental determined log(IC50) values. Results from the two models overlap well with each other, converging on the same scoring function, deprotonated charge state, and predicted the binding orientation for our collection of molecules.
Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Simulação por Computador , Descoberta de Drogas , Modelos Moleculares , Citocromo P-450 CYP2C9 , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Flurbiprofeno/química , Flurbiprofeno/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Varfarina/química , Varfarina/farmacologiaRESUMO
The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Piridonas/química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Animais , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Piridonas/síntese química , Piridonas/farmacologia , RNA Polimerase Dependente de RNA/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.
Assuntos
Disponibilidade Biológica , Desenho de Fármacos , Relação Estrutura-Atividade , Antivirais/farmacocinética , Química Farmacêutica , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C , Estrutura Molecular , RNA Polimerase Dependente de RNA , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).
Assuntos
RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Piridonas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Piridonas/administração & dosagem , Piridonas/química , Piridonas/farmacocinética , Relação Estrutura-AtividadeRESUMO
The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.
Assuntos
Antivirais/síntese química , Química Farmacêutica/métodos , Óxidos S-Cíclicos/síntese química , Piridazinas/química , Piridazinas/síntese química , Tiadiazinas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Antivirais/farmacologia , Células CACO-2 , Cristalografia por Raios X/métodos , Óxidos S-Cíclicos/farmacologia , RNA Polimerases Dirigidas por DNA/química , Desenho de Fármacos , Genótipo , Humanos , Concentração Inibidora 50 , Microssomos/metabolismo , Modelos Químicos , Conformação Molecular , Piridazinas/farmacologia , Relação Estrutura-Atividade , Tiadiazinas/farmacologiaRESUMO
Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b) <10 nM; EC(50) (1b)=34 nM) as well as good stability towards human liver microsomes (HLM t(1/2) =59 min).
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Piridazinas/síntese química , Piridazinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Estrutura Molecular , Piridazinas/química , Relação Estrutura-AtividadeRESUMO
4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).
Assuntos
Química Farmacêutica/métodos , Hepacivirus/enzimologia , Microssomos Hepáticos/enzimologia , Piridazinas/síntese química , Piridazinas/farmacologia , Tiazinas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Células CACO-2 , Cristalografia por Raios X/métodos , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Piridazinas/química , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologia , Fatores de TempoRESUMO
A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.