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1.
Food Chem ; 335: 127658, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32731124

RESUMO

Raphanus sativus var. longipinnatus, was exposed under experimental conditions to herbicides: rimsulfuron (RIM), administrated as (1) pure substance, (2) in commercially available formulation (RIMEL), (3) its degradation product: 4,6-dimethoxypyrimidin-2-amine (2ADP), (4) mesotrione (MES), (5) sulcotrione (SUL). Profiling and fingerprinting strategies, conducted by LC-MS/MS-FL, were employed to find markers of plant exposure to herbicide stress. The presence ofRIM metabolite in the tissues of plant exposed to this herbicide proved that it is necessary to determine both parent compound and its by-products to obtain reliable information on plant exposure to agrochemicals. A higher content of normetanephrine (NMN) (18-175%) and lower content of tyramine (TYR) (49-75%) and epinephrine (E) (75-83%) was observed in plant tissues exposed to RIM and 2ADP in comparison to blank sample. Therefore, NMN, TRY and E may be considered as markers of plant response to RIM. Non-target analysis enables to recognize the type of herbicide used during cultivation.


Assuntos
Herbicidas/toxicidade , Resíduos de Praguicidas/análise , Piridinas/toxicidade , Raphanus/química , Raphanus/efeitos dos fármacos , Sulfonamidas/toxicidade , Cromatografia Líquida , Cicloexanonas/farmacocinética , Cicloexanonas/toxicidade , Biomarcadores Ambientais , Epinefrina/análise , Mesilatos/farmacocinética , Mesilatos/toxicidade , Metaboloma , Normetanefrina/análise , Plantas Comestíveis/química , Plantas Comestíveis/efeitos dos fármacos , Piridinas/farmacocinética , Pirimidinas/toxicidade , Raphanus/metabolismo , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem , Tiramina/análise
2.
Cancer Treat Rev ; 89: 102062, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32659623

RESUMO

Cabozantinib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with advanced renal cell carcinoma (RCC) at a dose of 60 mg/day. As with other TKIs, cabozantinib is associated with high interpatient variability in drug clearance and exposure that can significantly impact safety and tolerability across a patient population. To optimize cabozantinib exposure (maintaining efficacy and tolerability) for the individual, patients may require treatment interruption with dose reduction (40 mg/day and then 20 mg/day). In the pivotal Phase 3 METEOR trial, cabozantinib significantly improved overall survival, progression-free survival and the objective response rate compared with everolimus in patients with advanced RCC who had received previous treatment with a VEGFR TKI. Dose reductions were common for patients receiving cabozantinib (60%) but effective as only 9% discontinued treatment due to adverse events (AEs). In this review, we discuss pharmacometric analyses that evaluated the impact of cabozantinib dose on efficacy and safety outcomes during the METEOR study. Exposure-response models demonstrate that the risk of experiencing adverse events and dose reduction is increased in patients with low cabozantinib clearance versus typical clearance and decreased in patients with high clearance. Dose reduction of cabozantinib to manage AEs is predicted to have minimal impact on efficacy as AEs are more likely to occur in patients with low clearance and higher exposure to cabozantinib. These analyses further support a dose modification strategy to optimize cabozantinib exposure for individual patients.


Assuntos
Anilidas/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/administração & dosagem , Anilidas/efeitos adversos , Anilidas/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renais/metabolismo , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Humanos , Neoplasias Renais/metabolismo , Modelos Estatísticos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Piridinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Proteína Tirosina Quinases/administração & dosagem , Receptores Proteína Tirosina Quinases/efeitos adversos , Receptores Proteína Tirosina Quinases/farmacocinética
3.
J Med Chem ; 63(13): 6876-6897, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32530624

RESUMO

Aldosterone synthase (CYP11B2) inhibitors have been explored in recent years as an alternative therapeutic option to mineralocorticoid receptor (MR) antagonists to reduce elevated aldosterone levels, which are associated with deleterious effects on various organ systems including the heart, vasculature, kidney, and central nervous system (CNS). A benzamide pyridine hit derived from a focused screen was successfully developed into a series of potent and selective 3-pyridyl isoindolin-1-ones CYP11B2 inhibitors. Our systematic structure-activity relationship study enabled us to identify unique structural features that result in high selectivity against the closely homologous cortisol synthase (CYP11B1). We evaluated advanced lead molecules, exemplified by compound 52, in an in vivo cynomolgus monkey acute adrenocorticotropic hormone (ACTH) challenge model and demonstrated a superior 100-fold in vivo selectivity against CYP11B1.


Assuntos
Citocromo P-450 CYP11B2/antagonistas & inibidores , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Desenho de Fármacos , Isoindóis/química , Piridinas/química , Piridinas/farmacologia , Administração Oral , Animais , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Estabilidade de Medicamentos , Humanos , Modelos Moleculares , Conformação Molecular , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Distribuição Tecidual
4.
Artigo em Inglês | MEDLINE | ID: mdl-32361632

RESUMO

Edoxaban is mainly enzymatically converted to a 4-carboxylic acid form (4CA-EDX) and an N-desmethyl form (ND-EDX) in humans. This study aimed to establish a simple liquid chromatography-tandem mass spectrometry method using core-shell octadecyl silica (ODS) microparticles for the simultaneous quantitation of edoxaban and its two major metabolites in human plasma. Analytes extracted from plasma specimens by a one-step deproteinization were separated using a 2.6-µm core-shell ODS microparticulate column and linear acetonitrile-ammonium acetate gradient elution at a flow rate of 0.25 mL/min with a run time of 7 min. The mass spectrometer was operated in the positive ion multiple reaction monitoring mode. Plasma samples collected from 20 patients with atrial fibrillation were analyzed by the present method. The chromatograms of drug-free human plasma had no interfering peaks. The calibration curves of edoxaban, 4CA-EDX, and ND-EDX were linear over the concentration ranges of 1.25-160, 0.47-60, and 0.12-15 ng/mL, respectively. Their pretreatment recoveries and matrix factors were 88.7-109.0% and 87.0-101.6%, respectively. The intra- and inter-day accuracy and imprecision values were 85.9-112.8% and within 13.3%, respectively. The plasma concentrations of edoxaban, 4CA-EDX, and ND-EDX in the patients had ranges of 17.8-102, 1.67-25.7, and 0.685-5.34 ng/mL, respectively. All the analytes were measurable within their calibration curves. In conclusion, this validated method for the simultaneous determination of edoxaban and its major metabolites was successfully applied to plasma specimens obtained from patients with atrial fibrillation.


Assuntos
Piridinas/sangue , Piridinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Tiazóis/sangue , Tiazóis/farmacocinética , Técnicas Biossensoriais , Coleta de Amostras Sanguíneas , Cromatografia Líquida de Alta Pressão , Humanos , Limite de Detecção , Metabolômica , Microesferas , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Dióxido de Silício/química
5.
J Med Chem ; 63(9): 4978-4996, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32369358

RESUMO

Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-ßR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a-c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.


Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Benzamidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Receptores de Ativinas Tipo I/genética , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Feminino , Células HEK293 , Humanos , Masculino , Camundongos SCID , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Mutação , Piperazinas/síntese química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Relação Estrutura-Atividade
6.
Cancer Chemother Pharmacol ; 85(5): 959-968, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32296873

RESUMO

PURPOSE: Isocitrate dehydrogenase (IDH) mutations lead to formation of the oncometabolite 2-hydroxyglutarate (2-HG), which is elevated in several solid and liquid tumors. Ivosidenib (AG-120) is a targeted, potent, oral inhibitor of the mutant IDH1 protein. We describe detailed pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation treated in a phase I study (ClinicalTrials.gov NCT02074839). METHODS: Patients received single and multiple oral doses of ivosidenib from 100 mg twice daily to 1200 mg once daily (QD) in 28-day continuous cycles. Concentrations of ivosidenib and 2-HG in plasma, and 2-HG in bone marrow, were assessed at routine intervals. Plasma 4ß-hydroxycholesterol/cholesterol ratios were assessed as a marker of CYP3A activity. RESULTS: Ivosidenib was rapidly absorbed and slowly eliminated (half-life 72-138 h) after single and multiple dosing. Ivosidenib exhibited dose- and time-dependent pharmacokinetics, with exposure increasing sub-proportionally to dose, and clearance increasing with increasing dose. Plasma 2-HG concentrations were maximally and persistently inhibited in the majority of patients receiving 500-mg QD ivosidenib, to concentrations close to those observed in healthy subjects. Ivosidenib pharmacokinetics were not affected by mild or moderate renal impairment, mild hepatic impairment, age, weight, sex, race, or co-administration of weak CYP3A4 inhibitors or inducers. Moderate-to-strong CYP3A4 inhibitors decreased ivosidenib clearance. Ivosidenib also induced CYP3A enzyme activity, with increases in 4ß-hydroxycholesterol/cholesterol ratios of 119-168% at 500-mg QD ivosidenib. CONCLUSIONS: Ivosidenib 500-mg QD has favorable pharmacokinetic and pharmacodynamic profiles in patients with advanced hematologic malignancies with an IDH1 mutation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02074839.


Assuntos
Glicina/análogos & derivados , Neoplasias Hematológicas , Isocitrato Desidrogenase , Piridinas , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Dose Máxima Tolerável , Mutação , Estadiamento de Neoplasias , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/farmacocinética , Resultado do Tratamento
7.
J Med Chem ; 63(9): 4896-4907, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32267685

RESUMO

Development of new photosensitizers (PSs) with high photodynamic efficacy and minimal side effects is of great interest in photodynamic therapy (PDT). In this work, we reported several pyridine-embedded phenothiazinium (pyridophenothiazinium) dyes, which could be conveniently synthesized in a few short steps and acted as highly efficient and potent PSs to selectively localize to lysosomes and photosensitively kill cancer cells. Among them, compound 5, which possessed the ability of promoting intracellular reactive oxygen species (ROS) upon light irradiation by almost 40-fold higher than that of methylene blue (MB, a general phenothiazinium-based PS), exhibited a remarkable phototherapeutic index (PI = 53.8) against HT29 cancer cells, leading to eradication of large solid tumors (∼300 mm3) in a xenograft mouse model without apparent side effects. These results suggest that the pyridophenothiazinium dyes developed herein, especially compound 5, may serve as promising lysosome-targeted PSs for efficient photodynamic antitumor therapy.


Assuntos
Antineoplásicos/uso terapêutico , Corantes/uso terapêutico , Lisossomos/metabolismo , Neoplasias/tratamento farmacológico , Fenotiazinas/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Corantes/síntese química , Corantes/farmacocinética , Corantes/efeitos da radiação , Feminino , Humanos , Luz , Masculino , Camundongos Endogâmicos BALB C , Fenotiazinas/síntese química , Fenotiazinas/farmacocinética , Fenotiazinas/efeitos da radiação , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/efeitos da radiação , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/efeitos da radiação , Piridinas/uso terapêutico , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Xenobiotica ; 50(9): 1115-1120, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32150479

RESUMO

Apatinib, a small molecule anti-angiogenic tyrosine kinase inhibitor is used extensively to treat advanced gastric cancer and simvastatin (SV) is often co-prescribed to treat cardiovascular disease in cancer patients. As both apatinib and SV are metabolized primarily by cytochrome P450 variant CYP3A4, they are likely to interact. Therefore, the potential effect of SV co-administration on pharmacokinetics of apatinib in Sprague-Dawley male rats is demonstrated for the first time.Sixteen rats were randomly divided into two groups (n = 8), 2 mg/kg SV orally co-administrated for seven days (group B) and the corresponding control group (group A). Apatinib concentrations of rat plasma samples were detected by ultra-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using non compartmental methods.Co-administration of SV for seven days significantly increased area under curve (AUC(0-t)), AUC(0-∞) and maximum plasma concentration of apatinib by 2.4-, 2.4-, and 2.7-fold, respectively while decreasing apparent volume of distribution and clearance by 81.7 and 73.9%, respectively.These findings suggest that concomitant administration of SV with 7 days may have inhibited the metabolism of apatinib in rats.


Assuntos
Piridinas/farmacocinética , Sinvastatina/farmacocinética , Animais , Área Sob a Curva , Cromatografia Líquida , Citocromo P-450 CYP3A , Inibidores de Proteínas Quinases , Piridinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Sinvastatina/administração & dosagem
10.
PLoS One ; 15(3): e0228339, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214351

RESUMO

The increased PD-L1 expression induces poorer prognosis in melanoma. The small molecule inhibitors of PD-1/PD-L1 pathways have been an encouraging drug development strategy because of good affinity and oral bioavailability without immunogenicity and immunotoxicities of PD-1/PD-L1 antibodies. In this study, we studied the effects of PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, on PD-1/PD-L1 binding and the cytokines secretion in human CD3+ cells in vitro. We also investigated the antitumor and immunomodulatory activity of PCC0208025 and the pharmacokinetics properties in B16-F10 melanoma-bearing mice. The results showed that PCC0208025 inhibited the PD-1/PD-L1 proteins binding, and rescued PD-L1-mediated inhibition of IFN-γ production in human CD3+ T cells in vitro. Furthermore, in B16-F10 melanoma-bearing mice, PCC0208025 presented the antitumor effects, enhanced IFN-γ levels in plasma, increased the frequency of CD3+CD8+ T and CD8+IFN-γ+ T and the ratios of CD8+/Treg, and deceased the CD4+CD25+CD127low/- (Treg) number in tumor. Pharmacokinetics study found that PCC0208025 was absorbed and distributed into the tumors with much higher concentrations than those of the blockade against PD-1/PD-L1 binding. Our work suggests that PCC0208025 exhibited anti-tumor effects through inhibiting Treg expansion and increasing cytotoxic activity of tumor-infiltrating CD8+ T cells by the blockade of PD-1/PD-L1 binding, which may provide the pharmacological basis to develop small molecule inhibitors of PD-1/PD-L1 binding for PCC0208025 as a lead compound.


Assuntos
Acetamidas/farmacologia , Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acetamidas/farmacocinética , Acetamidas/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Humanos , Fatores Imunológicos/farmacocinética , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Interferon gama/metabolismo , Masculino , Melanoma Experimental/patologia , Camundongos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico
11.
J Med Chem ; 63(6): 2915-2929, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32134643

RESUMO

To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/farmacocinética , Piridinas/farmacologia , Piridinas/farmacocinética , Administração Oral , Animais , Cães , Descoberta de Drogas , Feminino , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/química , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Fosforilação/efeitos dos fármacos , Piridinas/administração & dosagem , Piridinas/química
12.
PLoS One ; 15(2): e0228797, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32074133

RESUMO

(E)-N,N-dimethyl-4-oxo-4-(4-(pyridin-4-yl)phenyl)but-2-enamide hydrochloride (IMB-YH-4py5-2H) is a novel Protein Kinase B (PknB) inhibitor with potent activity against Mycobacterium tuberculosis strains. In the present study, a sensitive and specific liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine IMB-YH-4py5-2H in rat plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and separation was performed on an XTerra MS C18 column (2.1×50 mm, 3.5 µm) with gradient elution (methanol and 0.1% formic acid) at a flow rate of 0.3 mL/min. Detection was performed in multiple reaction monitoring (MRM) mode. Linear calibration curves were obtained over a concentration range of 1-100 ng/mL. The intra-day and inter-day precisions were lower than 8.46%, and the accuracies ranged from -8.71% to 12.36% at all quality control levels. The extraction recoveries were approximately 70%, and the matrix effects were negligible. All quality control samples were stable under different storage conditions. The validated method was successfully applied to a preclinical pharmacokinetic study in Sprague-Dawley rats. IMB-YH-4py5-2H demonstrated improved pharmacokinetic properties (higher exposure level) compared with its leading compound. IMB-YH-4py5-2H was also distributed throughout the lung pronouncedly, especially inside alveolar macrophages, indicating its effectiveness against lower respiratory infections.


Assuntos
Análise Química do Sangue/métodos , Cromatografia Líquida/métodos , Limite de Detecção , Piridinas/sangue , Piridinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Antituberculosos/sangue , Antituberculosos/isolamento & purificação , Antituberculosos/farmacocinética , Piridinas/isolamento & purificação , Ratos , Ratos Sprague-Dawley
13.
J Med Chem ; 63(4): 1724-1749, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32031803

RESUMO

We previously reported a milestone in the optimization of NBD-11021, an HIV-1 gp120 antagonist, by developing a new and novel analogue, NBD-14189 (Ref1), which showed antiviral activity against HIV-1HXB2, with a half maximal inhibitory concentration of 89 nM. However, cytotoxicity remained high, and the absorption, distribution, metabolism, and excretion (ADME) data showed relatively poor aqueous solubility. To optimize these properties, we replaced the phenyl ring in the compound with a pyridine ring and synthesized a set of 48 novel compounds. One of the new analogues, NBD-14270 (8), showed a marked improvement in cytotoxicity, with 3-fold and 58-fold improvements in selectivity index value compared with that of Ref1 and NBD-11021, respectively. Furthermore, the in vitro ADME data clearly showed improvements in aqueous solubility and other properties compared with those for Ref1. The data for 8 indicated that the pyridine scaffold is a good bioisostere for phenyl, allowing the further optimization of this molecule.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Piridinas/farmacologia , Pirróis/farmacologia , Tiazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Células CACO-2 , Células HEK293 , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/síntese química , Piridinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética
14.
J Med Chem ; 63(5): 2620-2637, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32081010

RESUMO

The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Administração Oral , Animais , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacocinética , Humanos , Masculino , Simulação de Acoplamento Molecular , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos Sprague-Dawley
15.
J Med Chem ; 63(6): 3028-3046, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32069401

RESUMO

PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.


Assuntos
Imidazóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Desenho de Fármacos , Feminino , Células HCT116 , Células HT29 , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/metabolismo
16.
Cancer Chemother Pharmacol ; 85(3): 593-604, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32008115

RESUMO

PURPOSE: This Phase I study evaluated the safety, tolerability, food effects, pharmacodynamics, and pharmacokinetics of donafenib in patients with advanced solid tumours. METHODS: Eligible patients received a single dose of donafenib (50 mg, 100 mg, 200 mg, 300 mg, or 400 mg) and were then observed over a 7-day period; thereafter, each patient received the corresponding dose of donafenib twice daily for at least 4 weeks. Safety assessment and pharmacokinetic sampling were performed for all patients at the given time points; preliminary tumour response was also assessed. RESULTS: Twenty-five patients were enrolled in this study. Gastrointestinal reactions were the most common treatment-related adverse event, followed by skin toxicity. The maximum tolerated dose (MTD) was 300 mg bid. The dose-limiting toxicities (DLTs) were grade 3 diarrhoea and fatigue at 300 mg bid and grade 3 skin toxicity at 400 mg bid. In the dose range of 100 ~ 400 mg, T1/2 and AUC0-t after multiple doses were 26.9 ~ 30.2 h and 189 ~ 356 h*µg/mL, respectively. Food did not have a significant effect on the pharmacokinetics of donafenib. Twenty-one patients were assessed for efficacy, and two patients achieved a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST), with a disease control rate of 57.1%. CONCLUSION: Oral donafenib was generally well tolerated and appeared to provide some clinical benefits; adverse events were manageable. Based on the results of this study, oral donafenib at 200 mg ~ 300 mg twice daily is recommended for further studies.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Interações Alimento-Droga/fisiologia , Neoplasias/tratamento farmacológico , Piridinas/administração & dosagem , Piridinas/farmacocinética , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Piridinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Pele/efeitos dos fármacos , Adulto Jovem
17.
Drug Metab Pharmacokinet ; 35(1): 151-159, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32007354

RESUMO

BACKGROUND: The anticoagulant actions of oral direct factor Xa (FXa) inhibitors can be inferred from their observed plasma concentrations; however, the steady-state pharmacokinetics (PK) of different FXa inhibitors have not been compared in clinically. METHODS: The sensitivity of the rivaroxaban, apixaban, and edoxaban in the STA-Liquid Anti-FXa assay were compared, and the anti-FXa plasma concentrations were measured for PK assessments. Nonlinear mixed-effects modeling was used to assess population PK in 329 patients with nonvalvular atrial fibrillation or venous thromboembolism. Patients were followed up for an average of 3.6 years. RESULTS: Sensitivity was similar among the three drugs in this assay, which could directly compare plasma concentrations instead of anti-FXa activities. Overall exposure was greatest in 5 mg BID apixaban relative to other drugs (p < 0.001). The geometric mean AUC for the 0 to 24-h interval was 4550 ng h/mL for apixaban, 2710 ng h/mL for 15 mg QD rivaroxaban, and 1290 ng h/mL for 60 mg QD edoxaban. The PKs of 2.5 mg BID apixaban or 15 mg QD rivaroxaban were associated with hemorrhagic events. CONCLUSIONS: Apixaban was associated with greater exposure, higher trough concentrations in plasma compared with rivaroxaban or edoxaban. Furthermore, a higher plasma concentration may partially predict hemorrhagic events.


Assuntos
Anticoagulantes/farmacocinética , Inibidores do Fator Xa/farmacocinética , Fator Xa/metabolismo , Pirazóis/farmacocinética , Piridinas/farmacocinética , Piridonas/farmacocinética , Rivaroxabana/farmacocinética , Tiazóis/farmacocinética , Idoso , Anticoagulantes/sangue , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Testes de Coagulação Sanguínea , Cromatografia Líquida , Inibidores do Fator Xa/sangue , Feminino , Humanos , Masculino , Estudos Prospectivos , Pirazóis/sangue , Piridinas/sangue , Piridonas/sangue , Rivaroxabana/sangue , Espectrometria de Massas em Tandem , Tiazóis/sangue , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/metabolismo
18.
Biomed Chromatogr ; 34(4): e4802, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31998982

RESUMO

Filgotinib is a selective JAK1 (Janus kinase) inhibitor, filed in Japan for the treatment of rheumatoid arthritis. In this paper, we report a validated liquid chromatography coupled with tandem mass spectrometry for the quantification of filgotinib in rat plasma using tofacitinib as an internal standard (IS) as per the Food and Drug Administration regulatory guidelines. Filgotinib and the IS were extracted from rat plasma using ethyl acetate as an extraction solvent and chromatographed using an isocratic mobile phase (0.2% formic acid:acetonitrile; 20:80, v/v) at a flow rate of 0.9 mL/min on a Gemini C18 column. Filgotinib and the IS were eluted at ~1.31 and 0.89 min, respectively. The MS/MS ion transitions monitored were m/z 426.3 → 291.3 and m/z 313.2 → 149.2 for filgotinib and the IS, respectively. The calibration range was 0.78-1924 ng/mL. No matrix effect and carryover were observed. Intra- and inter-day accuracies and precisions were within the acceptance range. Filgotinib was stable for three freeze-thaw cycles: on bench-top up to 6 h, in an autosampler up to 21 h, and at -80°C for 1 month. This novel method has been applied to a pharmacokinetic study in rats.


Assuntos
Cromatografia Líquida/métodos , Piridinas/sangue , Piridinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazóis/sangue , Triazóis/farmacocinética , Animais , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Piridinas/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Triazóis/química
19.
J Med Chem ; 63(3): 1397-1414, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31934767

RESUMO

Colony-stimulating factor 1 receptor (CSF-1R) is involved in inflammatory disorders as well as in many types of cancer. Based on high-throughput screening and docking results, we performed a detailed structure-activity-relationship study, leading to the discovery of a new series of compounds with nanomolar IC50 values against CSF-1R without the inhibition of fibroblast growth factor receptors. One of the most promising hits, compound 29, potently inhibited CSF-1R kinase with an IC50 value of 0.7 nM, while it showed no inhibition to the same family member FMS-like tyrosine kinase 3. Compound 29 displayed excellent anti-inflammatory effects against RAW264.7 macrophages indicated by significant inhibition against the activation of the CSF-1R pathway with low cytotoxicity. In addition, compound 29 exhibited strong in vivo anti-inflammatory efficacy alongside favorable drug characteristics. This novel compound 29 may serve as a new drug candidate with promising applications in inflammatory disorders.


Assuntos
Alquinos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Alquinos/síntese química , Alquinos/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Feminino , Inflamação/induzido quimicamente , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Células RAW 264.7 , Ratos Sprague-Dawley , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade
20.
J Med Chem ; 63(4): 1511-1525, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31951127

RESUMO

We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1. In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Transtorno do Espectro Autista/tratamento farmacológico , Benzodiazepinas/uso terapêutico , Piridinas/uso terapêutico , Receptores de Vasopressinas/metabolismo , Triazóis/uso terapêutico , Adolescente , Adulto , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Transtorno do Espectro Autista/metabolismo , Benzodiazepinas/síntese química , Benzodiazepinas/farmacocinética , Encéfalo/metabolismo , Criança , Ensaios Clínicos como Assunto , Descoberta de Drogas , Feminino , Humanos , Masculino , Mamíferos , Piridinas/síntese química , Piridinas/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinética
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