Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
Eur J Med Chem ; 189: 112064, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972393

RESUMO

Although a relatively wide range of therapeutic options is currently available for the treatment of HIV/AIDS, it is still among the most serious and virulent diseases and is associated with a high mortality rate. Integrase strand transfer inhibitors (INSTIs), e.g., FDA-approved dolutegravir (DTG), bictegravir (BIC) and cabotegravir (CAB), have recently been included in standard highly active antiretroviral therapy (HAART) schemes as one of the five major components responsible for the most beneficial clinical outcome. In this paper, we describe a combinatorial amide synthesis, biological evaluation and in silico modeling of new INSTIs containing heteroaromatic bioisosteric substitution instead of the well-studied halogen-substituted benzyl fragment. With the focus on the mentioned diversity point, a medium-sized library of compounds was selected for synthesis. A biological study revealed that many molecules were highly active INSTIs (EC50 < 10 nM). Two compounds 1{4} and 1{26} demonstrated picomolar antiviral activity that was comparable with CAB and were more active than DTG and BIC. Molecular docking study was performed to evaluate the binding mode of compounds in the active site of HIV-1 IN. In rats, lead compound 1{26} showed two-fold greater bioavailability than CAB and had a similar half-life. Compound 1{26} and its sodium salt were considerably more soluble in water than the parent drugs. Both molecules were very stable in human liver microsomes and plasma, demonstrated high affinity towards plasma proteins and did not show cytochrome (CYP) inhibition. This benefit profile indicates the great potential of these molecules as attractive candidates for subsequent evaluation as oral long-acting drugs and long-acting nanosuspension formulations for intramuscular injection.

2.
Artigo em Inglês | MEDLINE | ID: mdl-30283402

RESUMO

This article is to highlight the chemical properties and primary pharmacology of novel GPR119 agonist ZB-16 and its analogs, which were rejected during the screening. Experiments were performed in vitro (specific activity, metabolism and cell toxicity) and in vivo (hypoglycemic activity and pharmacokinetics). ZB-16 exhibits nanomolar activity (EC50 = 7.3-9.7 nM) on target receptor GPR119 in vitro associated with hypoglycemic activity in vivo. In animals with streptozotocin-nicotinamide induced type 2 diabetes mellitus (STZ-NA T2D) daily oral dose of ZB-16 (1 mg/kg) or sitagliptin (10 mg/kg) for 28 days resulted in the reduction of blood glucose levels. The effects of ZB-16 were comparable to the hypoglycemic action of sitagliptin. ZB-16 demonstrated relatively low plasma exposition, high distribution volume, mild clearance and a prolonged half-life (more than 12 h). The present study demonstrates that the targeted search for selective GPR119 receptor agonists is a well-founded approach for developing novel drugs for the therapy of T2D. Based on the combination of high in vitro activity (compared to competitor standards), a useful ADME profile, distinct hypoglycemic activity which is comparable to the efficacy of sitagliptin in rats with experimental T2D, and the acceptable pharmacokinetic profile, we recommend the ZB-16 compound for further research.

3.
Oncotarget ; 9(26): 18578-18593, 2018 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-29719628

RESUMO

Identification of molecular targets and mechanism of action is always a challenge, in particular - for natural compounds due to inherent chemical complexity. BP-Cx-1 is a water-soluble modification of hydrolyzed lignin used as the platform for a portfolio of innovative pharmacological products aimed for therapy and supportive care of oncological patients. The present study describes a new approach, which combines in vitro screening of potential molecular targets for BP-Cx-1 using Diversity Profile - P9 panel by Eurofins Cerep (France) with a search of possible active components in silico in ChEMBL - manually curated chemical database of bioactive molecules with drug-like properties. The results of diversity assay demonstrate that BP-Cx-1 has multiple biological effects on neurotransmitters receptors, ligand-gated ion channels and transporters. Of particular importance is that the major part of identified molecular targets are involved in modulation of inflammation and immune response and might be related to tumorigenesis. Characterization of molecular composition of BP-Cx-1 with Fourier Transform Ion Cyclotron Resonance Mass Spectrometry and subsequent identification of possible active components by searching for molecular matches in silico in ChEMBL indicated polyphenolic components, nominally, flavonoids, sapogenins, phenanthrenes, as the major carriers of biological activity of BP-Cx-1. In vitro and in silico target screening yielded overlapping lists of proteins: adenosine receptors, dopamine receptor DRD4, glucocorticoid receptor, serotonin receptor 5-HT1, prostaglandin receptors, muscarinic cholinergic receptor, GABAA receptor. The pleiotropic molecular activities of polyphenolic components are beneficial in treatment of multifactorial disorders such as diseases associated with chronic inflammation and cancer.

4.
Eur J Med Chem ; 99: 51-66, 2015 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-26046313

RESUMO

A series of novel highly active androgen receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile core was designed based on the SAR studies available from the reported AR antagonists and in silico modeling. Within the series, compound (R)-6 (ONC1-13B) and its related analogues, including its active N-dealkylated metabolite, were found to be the most potent molecules with the target activity (IC50, androgen-sensitive human PCa LNCaP cells) in the range of 59-80 nM (inhibition of PSA production). The disclosed hits were at least two times more active than bicalutamide, nilutamide and enzalutamide within the performed assay. Several compounds were classified as partial agonists. Hit-compounds demonstrated benefit pharmacokinetic profiles in rats. Comparative SAR and 3D molecular docking studies were performed for the hit compounds elucidating the observed differences in the binding potency.


Assuntos
Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/farmacologia , Desenho de Fármacos , Imidazolidinas/síntese química , Imidazolidinas/farmacologia , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/metabolismo , Antagonistas de Receptores de Andrógenos/farmacocinética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Imidazolidinas/metabolismo , Imidazolidinas/farmacocinética , Masculino , Simulação de Acoplamento Molecular , Conformação Proteica , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/química
5.
J Med Chem ; 57(18): 7716-30, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25148100

RESUMO

A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4025), with (S,S,S,S)-stereochemistry (EC50 = 3.4 ± 0.2 pM, HCV replicon genotype 1b), was dramatically more active than were the compounds with two (S)- and two (R)-chiral centers. Human serum did not significantly reduce the antiviral activity (<4-fold). Relatively favorable pharmacokinetic features and good oral bioavailability were observed during animal studies. Compound 13a was well tolerated in rodents (in mice, LD50 = 2326 mg/kg or higher), providing a relatively high therapeutic index. During safety, pharmacology and subchronic toxicity studies in rats and dogs, it was not associated with any significant pathological or clinical findings. This compound is currently being evaluated in phase I/II clinical trials for the treatment of HCV infection.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/metabolismo , Antivirais/farmacocinética , Antivirais/toxicidade , Chlorocebus aethiops , Ensaios Clínicos como Assunto , Cães , Feminino , Humanos , Imidazóis/metabolismo , Imidazóis/farmacocinética , Imidazóis/toxicidade , Masculino , Camundongos , Simulação de Acoplamento Molecular , Conformação Proteica , Ratos , Células Vero , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
6.
J Antimicrob Chemother ; 69(7): 1892-902, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24729605

RESUMO

OBJECTIVES: Development of a novel drug candidate with improved potency against influenza virus neuraminidase compared with currently available therapeutics, and high activity against oseltamivir-resistant viruses. METHODS: A number of synthetic compounds were evaluated for antiviral properties in vitro and in vivo. Three-dimensional molecular docking, assisted by a pharmacophore model, was applied to classify compounds within the series by their inhibitory potency. Compound stability in blood and in animal models was determined. Pharmacokinetic studies in dogs and rats after oral or intravenous administration were performed. RESULTS: A novel highly potent drug candidate [(3R,4R,5S)-5-[(diaminomethylene)amino]-3-(1-ethylpropoxy)-4-[(fluoroacetyl)amino]cyclohex-1-ene-1-carboxylic acid; AV5080] was synthesized and tested. AV5080 exhibited high activity against influenza virus neuraminidase in vitro, with IC(50) values of 0.03 nM and 0.07 nM against the neuraminidase of A/Duck/Minnesota/1525/1981/H5N1 and A/Perth/265/2009/H1N1 (wild-type), respectively. Notably, AV5080 was highly active against oseltamivir-resistant influenza viruses. CONCLUSIONS: Based on the results presented in this study, AV5080 is a promising novel oral drug candidate for the treatment of influenza, including oseltamivir-resistant types. Further pre-clinical development of AV5080 is warranted.


Assuntos
Antivirais/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Neuraminidase/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/farmacologia , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/enzimologia , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Virus da Influenza A Subtipo H5N1/enzimologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ratos
7.
J Cancer ; 5(2): 133-42, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24494031

RESUMO

Recently new drugs targeting androgen-dependent axis have been approved for the treatment of castration-resistant prostate cancer (CRPC) - Zytiga and Xtandi (formerly MDV3100), several other candidates (for example, ARN-509) are in early phases of clinical trials. However despite significant improvement in overall survival with new treatments it is evident that resistance to these drugs develops. One of the approaches to overcome it is combination therapy and from this point of view some potential for drug-drug interactions can limit the application of the drug. We describe here the preclinical development of ONC1-13B, antagonist of androgen receptor, with similar to MDV3100 and ARN-509 mechanism of action. It efficiently inhibits DHT-stimulated PSA expression and proliferation of prostate cancer cells, prevents binding of androgens to the AR ligand-binding domain, androgen-stimulated AR nuclear translocation and coactivator complex formation. In the LnCaP-Z2 xenograft model of prostate cancer ONC1-13B inhibits tumor growth and suppresses PSA expression. The in vivo activity of ONC1-13B is comparable to that of MDV3100 at similar doses, and even higher, calculated per unit of concentration in plasma. Distribution of ONC1-13B to the brain is less than that shown for MDV3100 and ARN-509, decreasing the risk of GABA-related seizure development. Additionally ONC1-13B induces significantly lower in vitro CYP3A activity than for example MDV3100 (known strong CYP3A inducer) or ARN-509 and could be well suited for co-therapy with drugs that are known CYP3A substrates. Thus ONC1-13B is a new promising antiandrogen demonstrating high efficacy in a preclinical model of prostate cancer, with lower potential for seizures and drug-drug interaction.

8.
J Antimicrob Chemother ; 69(5): 1311-24, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24428978

RESUMO

OBJECTIVES: Development of a novel drug candidate with improved activity against influenza virus neuraminidase (NA) compared with currently available therapeutics. METHODS: Synthesized compounds were evaluated in vitro and in vivo. Three-dimensional molecular docking was successfully applied to classify compounds within the series by inhibitory potency. Stability was investigated in blood samples and in animal models. A pharmacokinetic study was performed in dogs and rats using peroral and intravenous administration. RESULTS: A novel highly potent drug candidate [(3R,4R,5S)-4-(2,2-difluoroacetylamino)-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid; AV5027] and its prodrug ethyl ester (AV5075S) were synthesized and tested. AV5027 and AV5075S exhibit picomolar activity against influenza virus NA. AV5075S inhibited NA in a model of pneumonia using mouse-adapted A/Aichi/2/68 (H3N2) virus significantly more strongly than oseltamivir phosphate. A general metabolic pathway was constructed for the parent compound based on experimental results and theoretical analyses. CONCLUSIONS: AV5075S can be reasonably regarded as a novel 'next in class' oral drug candidate for the treatment of influenza.


Assuntos
Antivirais/administração & dosagem , Pró-Fármacos/administração & dosagem , Administração Intravenosa , Administração Oral , Animais , Modelos Animais de Doenças , Cães , Feminino , Masculino , Camundongos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ratos Sprague-Dawley , Resultado do Tratamento
9.
Bioorg Med Chem Lett ; 18(12): 3661-6, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18502121

RESUMO

Synthesis, biological evaluation, and SAR dependencies for a series of novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamide inhibitors of GSK-3beta kinase are described. The inhibitory activity of the synthesized compounds is highly dependent on the character of substituents in the phenyl ring and the nature of terminal heterocyclic fragment of the core molecular scaffold. The most potent compounds from this series contain 3,4-di-methyl or 2-methoxy substituents within the phenyl ring and 3-pyridine fragment connected to the 1,2,4-oxadiazole heterocycle. These compounds selectively inhibit GSK-3beta kinase with IC(50) value of 0.35 and 0.41 microM, respectively.


Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Glicogênio Sintase Quinase 3 beta , Concentração Inibidora 50 , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Bibliotecas de Moléculas Pequenas , Estereoisomerismo , Relação Estrutura-Atividade
10.
Mol Cell Biol ; 25(3): 1089-99, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15657435

RESUMO

Animal cells counteract oxidative stress and electrophilic attack through coordinated expression of a set of detoxifying and antioxidant enzyme genes mediated by transcription factor Nrf2. In unstressed cells, Nrf2 appears to be sequestered in the cytoplasm via association with an inhibitor protein, Keap1. Here, by using the yeast two-hybrid screen, human Keap1 has been identified as a partner of the nuclear protein prothymosin alpha. The in vivo and in vitro data indicated that the prothymosin alpha-Keap1 interaction is direct, highly specific, and functionally relevant. Furthermore, we showed that Keap1 is a nuclear-cytoplasmic shuttling protein equipped with a nuclear export signal that is important for its inhibitory action. Prothymosin alpha was able to liberate Nrf2 from the Nrf2-Keap1 inhibitory complex in vitro through competition with Nrf2 for binding to the same domain of Keap1. In vivo, the level of Nrf2-dependent transcription was correlated with the intracellular level of prothymosin alpha by using prothymosin alpha overproduction and mRNA interference approaches. Our data attribute to prothymosin alpha the role of intranuclear dissociator of the Nrf2-Keap1 complex, thus revealing a novel function for prothymosin alpha and adding a new dimension to the molecular mechanisms underlying expression of oxidative stress-protecting genes.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Estresse Oxidativo/genética , Precursores de Proteínas/metabolismo , Proteínas/metabolismo , Timosina/análogos & derivados , Timosina/metabolismo , Transativadores/metabolismo , Ativação Transcricional/genética , Transporte Ativo do Núcleo Celular/genética , Transporte Ativo do Núcleo Celular/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo/fisiologia , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Ativação Transcricional/fisiologia , Células Tumorais Cultivadas , Técnicas do Sistema de Duplo-Híbrido
11.
J Immunol Methods ; 266(1-2): 185-96, 2002 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12133636

RESUMO

To overcome poor immunogenicity of prothymosin alpha, a small and highly acidic nuclear protein involved in cell proliferation, production of anti-prothymosin alpha antibodies in mice immunized with free human prothymosin alpha, with prothymosin alpha coupled to different carriers and with prothymosin alpha fused to green fluorescent protein was assessed. Fusing prothymosin alpha to green fluorescent protein turned out to be the superior approach resulting in production of high titer anti-prothymosin alpha antibodies. From these studies, two highly specific anti-prothymosin alpha monoclonal antibodies recognizing epitopes within the amino terminal (2F11) and middle (4F4) portions of the human prothymosin alpha molecule were obtained and characterized. As expected, the 2F11 antibody displayed broad species specificity, whereas the 4F4 antibody appeared to be species-specific permitting discrimination of human versus rat protein. Furthermore, a combination of point mutations in prothymosin alpha that alter the properties of the protein precluded recognition by the 4F4 antibody. Intramolecular masking of the 4F4 epitope in prothymosin alpha fused to the Tat transduction peptide of human immunodeficiency virus type 1 was observed. The anti-prothymosin alpha antibodies obtained were suitable for precipitation of human prothymosin alpha from HeLa cell lysates and for immunolocalization of the endogenous prothymosin alpha within the cells. Fusion with green fluorescent protein may thus be helpful in raising antibodies against 'problematic' proteins.


Assuntos
Anticorpos Monoclonais/imunologia , Precursores de Proteínas/imunologia , Timosina/análogos & derivados , Timosina/imunologia , Animais , Especificidade de Anticorpos , Mapeamento de Epitopos , Produtos do Gene tat/genética , Proteínas de Fluorescência Verde , Células HeLa , Humanos , Proteínas Luminescentes/genética , Camundongos , Camundongos Endogâmicos BALB C , Mutação Puntual , Conformação Proteica , Precursores de Proteínas/química , Precursores de Proteínas/genética , Proteínas Recombinantes de Fusão/imunologia , Especificidade da Espécie , Timosina/química , Timosina/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA