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1.
Bioorg Med Chem Lett ; 26(2): 429-434, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26684851

RESUMO

As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Antipsicóticos/uso terapêutico , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Receptor de Glutamato Metabotrópico 5/metabolismo , Esquizofrenia/tratamento farmacológico , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Células HEK293 , Humanos , Masculino , Pirazinas/química , Pirazinas/farmacocinética , Pirazóis/química , Pirazóis/farmacocinética , Ratos Sprague-Dawley , Esquizofrenia/metabolismo
2.
Bioorg Med Chem Lett ; 25(6): 1310-7, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25683622

RESUMO

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.


Assuntos
Antipsicóticos/química , Compostos Heterocíclicos com 2 Anéis/química , Imidazóis/química , Pirimidinonas/química , Receptor de Glutamato Metabotrópico 5/química , Regulação Alostérica , Animais , Antipsicóticos/síntese química , Antipsicóticos/farmacocinética , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Humanos , Imidazóis/síntese química , Imidazóis/farmacocinética , Locomoção/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ligação Proteica , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-Atividade
3.
Rev. argent. reumatolg. (En línea) ; 33(4): 188-198, oct. 2022. tab, graf
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1449423

RESUMO

Introducción: el lupus eritematoso sistémico (LES) es una enfermedad sistémica que se ha asociado a mayor severidad con la infección por SARS-CoV-2. Particularmente la alta actividad de la enfermedad y algunos inmunosupresores se han vinculado a peores desenlaces. Objetivos: describir las características por SARS-CoV-2 en pacientes con LES en Argentina del registro SAR-COVID y establecer los factores asociados a peor desenlace de la misma. Materiales y métodos: estudio observacional. Se incluyeron pacientes con diagnóstico de LES con infección confirmada por SARS-CoV-2 (RT-PCR y/o serología positiva) del registro SAR-COVID. Los datos se recolectaron desde agosto de 2020 hasta marzo de 2022. El desenlace de la infección se midió mediante la escala ordinal de la Organización Mundial de la Salud (EO-OMS). Se definió COVID-19 severo con un valor EO-OMS ≥5. Análisis descriptivo, test T de Student, test de Mann Whitney U, ANOVA, chi2 y Fisher. Regresión logística múltiple. Resultados: se incluyeron 399 pacientes, el 93% de sexo femenino, con una edad media de 40,9 años (DE 12,2). El 39,6% tenía al menos una comorbilidad. Al momento de la infección, el 54,9% recibía glucocorticoides, el 30,8% inmunosupresores y el 3,3% agentes biológicos. La infección por SARS-CoV-2 fue leve en la mayoría de los casos, mientras que un 4,6% tuvo curso severo y/o falleció. Estos últimos presentaban comorbilidades, usaban glucocorticoides y tenían síndrome antifosfolipídico (SAF) con mayor frecuencia y mayor actividad de la enfermedad al momento de la infección. En el análisis multivariado, la hipertensión arterial, el diagnóstico de SAF y el uso de glucocorticoides se asociaron a hospitalización severa y/o muerte por COVID-19 (EO-OMS ≥5). Conclusiones: en esta cohorte de pacientes con LES con infección por SARS-CoV-2 confirmada, la mayoría cursó de manera sintomática, un 22,1% fue hospitalizado y un 5% requirió ventilación mecánica. La mortalidad fue cercana al 3%. El diagnóstico de SAF, tener hipertensión arterial y el uso de glucocorticoides se asociaron significativamente con COVID-19 severo.


Introduction: systemic lupus erythematosus (SLE) is a systemic disease that has been associated with greater severity with SARS-CoV-2 infection. Particularly high disease activity and some immunosuppressants have been linked to worse outcomes. Objectives: to describe the characteristics due to SARS-CoV-2 in patients with SLE in Argentina from the SAR-COVID registry and to establish the factors associated with a worse outcome of the same. Materials and methods: observational study. Patients diagnosed with SLE with confirmed SARS-CoV-2 infection (RT-PCR and/or positive serology) from the SAR-COVID registry were included. Data was collected from August 2020 to March 2022. The outcome of the infection was measured using the World Health Organization - ordinal scale (WHO-OS). Severe COVID-19 was defined as an WHO-OS value ≥5. Descriptive analysis, Student's T test, Mann Whitney U, ANOVA, chi2 and Fisher. Multiple logistic regression. Results: a total of 399 patients were included, 93% female, with a mean age of 40.9 years (SD 12.2), 39.6% had at least one comorbidity. At the time of infection, 54.9% were receiving glucocorticoids, 30.8% immunosuppressants, and 3.3% biological agents. SARS-CoV-2 infection was mild in most cases, while 4.6% had a severe course and/or died. The latter had comorbidities, used glucocorticoids and had antiphospholipid syndrome (APS) more frequently and higher disease activity at the time of infection. In the multivariate analysis, high blood pressure, the diagnosis of APS, and the use of glucocorticoids were associated with severe hospitalization and/or death from COVID-19 (WHO-EO ≥5). Conclusions: in this cohort of SLE patients with confirmed SARS-CoV-2 infection, most had a symptomatic course, 22.1% were hospitalized, and 5% required mechanical ventilation. Mortality was close to 3%. The diagnosis of APS, having high blood pressure, and the use of glucocorticoids were significantly associated with severe COVID-19.


Assuntos
Pandemias
4.
J Med Chem ; 58(2): 978-93, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25495129

RESUMO

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.


Assuntos
Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases , Administração Oral , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Ratos , Ratos Wistar , Esquizofrenia/tratamento farmacológico , Relação Estrutura-Atividade
5.
Toxicology ; 175(1-3): 167-75, 2002 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-12049845

RESUMO

Four terpenylnaphthoquinones were found to enhance the rate of superoxide production in the presence of ascorbate as detected from the superoxide dismutase (SOD)-inhibitable initial oxygen consumption rates. Initial rates of oxygen consumption in the presence of ascorbate plus quinone increase with an increase in the half-wave reduction potentials of the quinones. These quinones also enhance the rate of Cyt(III)c reduction by xanthine/xanthine oxidase (X/XO) in both air- and nitrogen-saturated aqueous solutions at pH 7.4. Maximum rates of Cyt(III)c reduction in nitrogen and oxygen-saturated solutions (V(max)), in the presence of X/XO, increase with an increase in the half-wave reduction potentials of the quinones. SOD inhibits Cyt(III)c reduction rates in the presence of these quinones and X/XO in a manner which is also dependent on the quinone half-wave redox potential. The relative antineoplastic activity of two of these quinones follows the order in rates of oxygen consumption or Cyt(III)c reduction. This is consistent with an antineoplastic action of these quinones through the mechanism of redox cycling or possible interference or inhibition of mitochondrial respiration.


Assuntos
Ácido Ascórbico/química , Naftoquinonas/química , Terpenos/química , Animais , Grupo dos Citocromos c/química , Espectroscopia de Ressonância de Spin Eletrônica , Cavalos , Cinética , Oxirredução , Superóxido Dismutase/química , Superóxidos/química , Xantina/química , Xantina Oxidase/química
6.
J Med Chem ; 57(10): 4196-212, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24758746

RESUMO

We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.


Assuntos
Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Administração Oral , Animais , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Ratos , Relação Estrutura-Atividade
7.
Bioorg Med Chem ; 14(8): 2816-27, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16376545

RESUMO

Several 2-arylamino-, 2-aryloxy- and 2-arylsulfanyl-6(7)-alkyl-1,4-naphthoquinones (NQ) have been prepared and further transformed into the corresponding heterocyclic-fused naphthoquinones by palladium (II)-catalyzed oxidative cyclization. The compounds synthesized have been evaluated against neoplastic cell lines. The extension of the polycyclic system clearly decreased the cytotoxic potency of the 2-substituted terpenylnaphthoquinones.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas de Bombardeamento Rápido de Átomos
8.
Bioorg Med Chem ; 13(3): 631-44, 2005 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-15739276

RESUMO

Several 6(7)-alkyl-1,4-naphthoquinones (NQ) have been prepared by cycloaddition reactions between the monoterpene alpha-myrcene and p-benzoquinones and halogen and nitrogen-containing functional groups have been introduced at the C-2 position of the naphthoquinone ring via nucleophilic addition or substitution reactions. These substituents at positions 2/3 of the NQ clearly influence the cytotoxic potency of this type of compound. Of particular interest is substitution by arylamino, specifically p-oxyarylamino, groups, which considerably enhance their bioactivity and selectivity.


Assuntos
Quinonas/síntese química , Terpenos/química , Espectroscopia de Ressonância Magnética , Quinonas/toxicidade , Espectrofotometria Infravermelho
9.
Arch Pharm (Weinheim) ; 335(9): 427-37, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12447916

RESUMO

Various Diels Alder cycloaddition conditions have been used to optimise the preparation of cytotoxic 6-alkyl-1, 4-naphthoquinones, which were subsequently transformed into 6(7)-alkyl-2-hydroxy-1, 4-naphthoquinones. The compounds thus prepared were evaluated for their cytotoxic activity against several neoplastic cultured cell lines and some of them showed IC50 values below the microM level.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Animais , Antineoplásicos/química , Divisão Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Naftoquinonas/química , Ratos , Células Tumorais Cultivadas
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