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1.
Mol Cell Biochem ; 458(1-2): 39-47, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30905023

RESUMO

The development of new antihyperlipidemic agents with higher potency and lower side effects is of high priority. In this study, 1,3,4 thiadiazole Schiff base derivatives were synthesized as potential peroxisome proliferation-activated receptor-α (PPARα) agonists and characterized using elemental analysis, FTIR, 1H-NMR, 13C-NMR and mass spectroscopy and then tested for their hypolipidemic activity in Triton WR-1339-induced acute hyperlipidemic rat model in comparison with bezafibrate. The compounds showed significant hypolipidemic activity. Induced fit docking showed that the compounds are potential activators of PPARα with binding scores - 8.00 Kcal/mol for 2,5-bis(4-hydroxybenzylidenamino)-1,3,4-thiadiazole. PCR array analysis showed an increase in the expression of several genes involved in lipid metabolism through mitochondrial fatty acid ß oxidation and are part of PPARα signaling pathway including Acsm3, Fabp4 and Hmgcs1. Gene expression of Lrp12 and Lrp1b involved in LDL uptake by liver cells and Cyp7a1 involved in cholesterol catabolism were also found to be upregulated.


Assuntos
Hiperlipidemias/tratamento farmacológico , Hipolipemiantes , PPAR alfa/agonistas , Tiadiazóis , Doença Aguda , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Masculino , PPAR alfa/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Tiadiazóis/química , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologia
2.
Biopharm Drug Dispos ; 39(8): 388-393, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30175851

RESUMO

PF-06456384 is an extremely potent and selective blocker of the Nav 1.7 sodium channel designed as a potential intravenous (i.v.) analgesic targeting high potency and rapid clearance to minimize the potential for residual effects following the end of infusion. In our previous experience targeting oral molecules, the requirement to obtain potent, Nav 1.7 selective molecules led to a focus on acidic, amphipilic compounds cleared primarily by organic anion-transporting polypeptide mediated hepatic uptake and subsequent biliary excretion. However, the physicochemical properties of the i.v. lead matter were substantially different, moving from acidic, amphiphilic chemical space to zwitterions as well as substantially increasing molecular weight. This report describes the continued relevance of organic anion-transporting polypeptide driven hepatic uptake in this physicochemical space and highlights an apparent impact of the formulation excipient Solutol on the clearance and distribution of PF-06456384.


Assuntos
Transportadores de Ânions Orgânicos/metabolismo , Piperidinas/farmacocinética , Piridinas/farmacocinética , Tiadiazóis/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Animais , Interações Medicamentosas , Excipientes/farmacocinética , Masculino , Canal de Sódio Disparado por Voltagem NAV1.7 , Polietilenoglicóis/farmacocinética , Ratos Wistar , Ácidos Esteáricos/farmacocinética
3.
Tuberculosis (Edinb) ; 112: 37-44, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30205967

RESUMO

One lead 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole was identified as an inhibitor of shikimate dehydrogenase with antitubercular activity. Following up this compound, we optimized the lead through systematic modification of the 3 and 6 positions. The antitubercular activities in vitro, shikimate dehydrogenase inhibitory activities and cytotoxicity of derivatives were determined. We found IMB-SD62 with lower cytotoxicity and better activity. Thus, we studied the in vivo efficacy of IMB-SD62 against Mycobacterium tuberculosis and pharmacokinetics of IMB-SD62. In vivo acute M. tuberculosis H37Rv infection assay, IMB-SD62 showed antitubercular activity with the mean lung CFU counts decreasing 1.7 lg. The plasma pharmacokinetics study in rats showed that the oral bioavailability of IMB-SD62 was 14% and the half time was 1.05 h. The results of tissue distribution indicated that IMB-SD62 was mainly absorbed by liver and lung. In vitro metabolism study suggested that the metabolic ways of IMB-SD62 were dealkylated, oxidized and demethylated. CYP enzyme inhibition of IMB-SD62 in human liver microsomes was also evaluated. IMB-SD62 showed barely inhibition on CYP3A4 and CYP2D6. The excretion study manifested that IMB-SD62 was mainly eliminated by fecal excretion in rats. We concluded that based on these pharmaceutical properties, IMB-SD62 has the potential to be developed into new TB drug.


Assuntos
Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiadiazóis/farmacologia , Tuberculose Pulmonar/tratamento farmacológico , Administração Oral , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/metabolismo , Animais , Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Disponibilidade Biológica , Biotransformação , Modelos Animais de Doenças , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Fezes/química , Haplorrinos , Humanos , Eliminação Intestinal , Masculino , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Mycobacterium tuberculosis/enzimologia , Ratos Sprague-Dawley , Tiadiazóis/administração & dosagem , Tiadiazóis/farmacocinética , Distribuição Tecidual , Tuberculose Pulmonar/microbiologia
4.
J Proteome Res ; 17(7): 2428-2439, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29750532

RESUMO

Targeted therapy of hepatocellular carcinoma (HCC) is essential for improved therapies. Therefore, identification of key targets specifically to HCC is an urgent requirement. Herein, an iTRAQ quantitative proteomic approach was employed to identify differentially expressed proteins in HCC tumor tissues. Of the upregulated tumor-related proteins, minichromosome maintenance 2 (MCM2), a DNA replication licensing factor, was one of the most significantly altered proteins, and its overexpression was confirmed using tissue microarray. Clinicopathological analysis of multiple cohorts of HCC patients indicated that overexpression of MCM2 was validated in 89.8% tumor tissues and strongly correlated with clinical stage. Furthermore, siRNA-mediated repression of MCM2 expression resulted in significant suppression of the HepG2 cell cycle and proliferation through the cyclin D-dependent kinases (CDKs) 2/7 pathway. Finally, the first small molecule-based MCM2-targeted NIR-II probe CH1055-MCM2 was concisely generated and subsequently evaluated in mice bearing HepG2 xenografts. The excellent imaging properties such as good tumor uptake and high tumor contrast and specificity were achieved in the small animal models. This analytical strategy can determine novel accessible targets of HCC useful for imaging and therapy.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Corantes Fluorescentes/análise , Componente 2 do Complexo de Manutenção de Minicromossomo/análise , Proteômica/métodos , Animais , Carcinoma Hepatocelular/química , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Quinases Ciclina-Dependentes , Células Hep G2/transplante , Xenoenxertos , Humanos , Neoplasias Hepáticas/química , Neoplasias Hepáticas/diagnóstico , Camundongos , Componente 2 do Complexo de Manutenção de Minicromossomo/metabolismo , Fenilpropionatos/farmacocinética , Tiadiazóis/farmacocinética
5.
J Clin Pharmacol ; 58(12): 1557-1565, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29746725

RESUMO

DS-2969b is a novel GyrB inhibitor in development for the treatment of Clostridium difficile infection. The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on normal gastrointestinal microbiota groups of single daily oral ascending doses of DS-2969b in healthy subjects. The study enrolled 6 sequential ascending dose cohorts (6 mg, 20 mg, 60 mg, 200 mg, 400 mg, and 600 mg). In each cohort, 6 subjects were administered DS-2969b and 2 subjects were administered matching placebo. DS-2969b was safe and well tolerated at all dose levels examined. All adverse events related to DS-2969b were mild to moderate in severity and predominantly related to the gastrointestinal tract. DS-2969a (free form of DS-2969b) plasma concentrations increased with increasing doses; however, both the maximum serum concentration and area under the plasma concentration-time curve generally increased less than dose proportionally. DS-2969a was predominantly eliminated in the urine, with feces as a minor route of elimination. While the overall proportion of DS-2969a eliminated in the feces was low, target fecal levels sufficient for C. difficile eradication were achieved within 24 hours of administration with doses of 60 mg or higher. In exploratory analyses, DS-2969b appeared to reduce bacterial counts in 8 of the 25 groups of normal intestinal microbiota examined, suggesting that DS-2969b has only a mild effect on intestinal microbiota. Data from this study support and encourage further development of DS-2969b as a novel treatment for C. difficile infection.


Assuntos
Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Tiadiazóis/efeitos adversos , Tiadiazóis/farmacocinética , Inibidores da Topoisomerase II/efeitos adversos , Inibidores da Topoisomerase II/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Bactérias/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Meia-Vida , Humanos , Imidazóis/administração & dosagem , Imidazóis/sangue , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Piperidinas/administração & dosagem , Piperidinas/sangue , Tiadiazóis/administração & dosagem , Tiadiazóis/sangue , Inibidores da Topoisomerase II/administração & dosagem , Inibidores da Topoisomerase II/sangue , Adulto Jovem
6.
Neuropharmacology ; 133: 129-144, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29407765

RESUMO

Xanomeline (3-(Hexyloxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole) is a muscarinic agonist that is considered to be functionally selective for the M1/M4 receptor subtypes. Part of xanomeline binding is resistant to washing. Wash-resistant xanomeline activates muscarinic receptors persistently, except for the M5 subtype. Mutation of leucine 6.46 to isoleucine at M1 or M4 receptors abolished persistent activation by wash-resistant xanomeline. Reciprocal mutation of isoleucine 6.46 to leucine at the M5 receptor made it sensitive to activation by wash-resistant xanomeline. Lowering of membrane cholesterol made M1 and M4 mutants and M5 wild type receptors sensitive to activation by wash-resistant xanomeline. Molecular docking revealed a cholesterol binding site in the groove between transmembrane helices 6 and 7. Molecular dynamics showed that interaction of cholesterol with this binding site attenuates receptor activation. We hypothesize that differences in cholesterol binding to this site between muscarinic receptor subtypes may constitute the basis for xanomeline apparent functional selectivity and may have notable therapeutic implications. Differences in receptor-membrane interactions, rather than in agonist-receptor interactions, represent a novel possibility to achieve pharmacological selectivity. Our findings may be applicable to other G protein coupled receptors.


Assuntos
Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Colesterol/metabolismo , Agonistas Muscarínicos/farmacocinética , Piridinas/farmacocinética , Receptores Muscarínicos/metabolismo , Tiadiazóis/farmacocinética , Animais , Células CHO/citologia , Cálcio/metabolismo , Cricetulus , Citometria de Fluxo , Fosfatos de Inositol/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Simulação de Acoplamento Molecular , Ensaio Radioligante , Receptores Muscarínicos/genética , Trítio/farmacocinética
7.
Plant Physiol Biochem ; 118: 370-376, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28710944

RESUMO

The plant activator acibenzolar-S-methyl (BTH) undergoes phototransformation when exposed to solar radiation. Here we investigated the changes in its elicitation properties on BY-2 tobacco cells at different stages of the photochemical reaction. Both pure BTH and formulated BTH were irradiated in controlled conditions to achieve different extents of conversion. Both pure BTH (900 µM) and Bion® (0.4 g.L-1) induced BY-2 cell death, but BTH photoconverted to an extent of 25 ± 3% lowered the cell death rate. A kinetic study of ß-1,3-glucanase and chitinase activities was conducted on BY-2 extracellular medium. Exposure of tobacco cells to either pure BTH or Bion® resulted in a significant increase in the activities of both defense enzymes, which peaked 48 h after the treatment. The pathogenesis-related (PR) protein activities were quantified 48 h after elicitation for a range of phototransformed BTH solutions. The enzyme activities were reduced when BY-2 cells were treated with solutions in which BTH conversion was 22 ± 3%, 42 ± 3% and 100 ± 3%, but were not affected by the solution in which BTH was phototransformed at 60%, suggesting that some of the secondary photoproducts also exhibit eliciting properties. Solar irradiation of BTH thus impairs its elicitation properties, but this impairment depends strongly on the extent of phototransformation.


Assuntos
Células Vegetais/metabolismo , Tiadiazóis , Tabaco/metabolismo , Biotransformação , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologia
8.
Brain ; 140(3): 764-780, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28087578

RESUMO

Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer's disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer's disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick's disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies.


Assuntos
Encéfalo , Carbolinas/farmacocinética , Emaranhados Neurofibrilares/patologia , Tomografia por Emissão de Pósitrons , Tauopatias , Proteínas tau/metabolismo , Autorradiografia , Benzotiazóis/química , Benzotiazóis/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Butadienos/farmacocinética , Diagnóstico , Feminino , Fluorescência , Humanos , Masculino , Fenazopiridina/farmacocinética , Ensaio Radioligante , Compostos Radiofarmacêuticos/farmacocinética , Tauopatias/diagnóstico por imagem , Tauopatias/metabolismo , Tauopatias/patologia , Tiadiazóis/farmacocinética
9.
Cancer Chemother Pharmacol ; 79(2): 315-326, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28097385

RESUMO

PURPOSE: This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. METHODS: Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125-16 mg/m2/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. RESULTS: One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/m2/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. CONCLUSIONS: On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/m2/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/m2/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle.


Assuntos
Cinesina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Sulfonamidas/administração & dosagem , Tiadiazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Polietilenoglicóis , Proteínas Recombinantes/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Tiadiazóis/efeitos adversos , Tiadiazóis/farmacocinética
10.
J Clin Endocrinol Metab ; 101(2): 417-26, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26653113

RESUMO

CONTEXT: Women's health disorders are commonly treated by agents that suppress the hypothalamic-pituitary-gonadal axis. NK3 receptor antagonism modulates this axis with distinct pharmacology compared to existing therapies. OBJECTIVE: The study aim was to evaluate safety, pharmacokinetics, and pharmacodynamics on gonadotropins and sex hormones after single- and multiple-dose administration of an NK3R antagonist to healthy men and women. DESIGN AND SETTING: This was a first-in-human, double-blind, placebo-controlled, combined single and multiple ascending dose trial. PARTICIPANTS: Forty-one men and 24 regularly cycling women participated in the study. INTERVENTION(S): In part 1 of the study, men received single oral doses of 3-180 mg or placebo. In part 2, men received placebo or 20, 60, or 180 mg each day for 10 days. In part 3, women received placebo or 20, 60, or 180 mg each day for 21 days, where dosing was initiated on day 3 ± 2 after menses. MAIN OUTCOME MEASURE(S): Safety, tolerability, pharmacokinetics, and pharmacodynamics on circulating levels of LH, FSH, testosterone, estradiol, and progesterone, in addition to physiological biomarkers of endometrial thickening, follicle growth, and the duration of the menstrual cycle were evaluated. RESULTS: ESN364 was well-tolerated and rapidly bioavailable with linear pharmacokinetics and no drug accumulation with repeated, daily oral administration. Drug treatment dose-dependently decreased basal LH, but not FSH, and consequently decreased estradiol and progesterone (in women) as well as testosterone (in men). The hormonal changes in women corresponded to delayed ovulation, decreased endometrial thickening, impeded follicular maturation, and prolongation of the menstrual cycle. Drug effects were rapidly reversible. CONCLUSIONS: Oral administration of the NK3R antagonist, ESN364, suppressed the hypothalamic-pituitary-gonadal axis in healthy volunteers by selective modulation of gonadotropin secretion, leading to a restrained decrease in ovarian hormone levels in women. These results suggest that ESN364 may offer therapeutic benefit in the treatment of women's health disorders with a mitigated risk of menopausal-like adverse events.


Assuntos
Hormônios Esteroides Gonadais/antagonistas & inibidores , Compostos Heterocíclicos com 2 Anéis/farmacologia , Antagonistas de Hormônios/farmacologia , Receptores da Neurocinina-3/antagonistas & inibidores , Tiadiazóis/farmacologia , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Endométrio/efeitos dos fármacos , Feminino , Hormônios Esteroides Gonadais/metabolismo , Gonadotropinas/sangue , Gônadas/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/efeitos adversos , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Antagonistas de Hormônios/efeitos adversos , Antagonistas de Hormônios/farmacocinética , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Ciclo Menstrual/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/crescimento & desenvolvimento , Ovulação/efeitos dos fármacos , Tiadiazóis/efeitos adversos , Tiadiazóis/farmacocinética , Adulto Jovem
11.
Bioorg Med Chem ; 23(10): 2424-34, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25868746

RESUMO

Kinesin spindle protein (KSP) is a mitotic kinesin that is expressed only in proliferating cells and plays a key role in spindle pole separation, formation of a bipolar mitotic spindle, as well as centrosome separation and maturation. Inhibition of KSP has the potential to provide anti-tumor activity while avoiding peripheral neuropathy associated with some microtubule-targeted drugs. Based on MK-0731 and related heterocyclic compounds targeting the KSP monastrol binding site, structurally constrained spiro-cyclic KSP inhibitors were designed. In particular, rapid evaluation and optimization of the novel spiro 1,3,4-thiadiazolines resulted in a series of potent KSP inhibitors demonstrating mechanism based activities in cells, including induction of the mitotic marker phospho-histone H3 and induction of monaster spindle formation. Further optimization of the pharmacokinetic (PK) properties afforded MK-8267 as a potent, orally bioavailable and brain penetrant KSP inhibitor which showed anti-tumor activity in preclinical xenograft models.


Assuntos
Antineoplásicos/síntese química , Neoplasias Encefálicas/tratamento farmacológico , Cinesina/antagonistas & inibidores , Compostos de Espiro/síntese química , Tiadiazóis/síntese química , Moduladores de Tubulina/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Biomarcadores/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Cães , Descoberta de Drogas , Células HCT116 , Histonas/metabolismo , Humanos , Cinesina/genética , Cinesina/metabolismo , Masculino , Camundongos , Permeabilidade , Piperidinas/química , Pirimidinas/química , Pirróis/química , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologia , Tionas/química , Moduladores de Tubulina/farmacocinética , Moduladores de Tubulina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Med Chem ; 58(10): 4278-90, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25905990

RESUMO

An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).


Assuntos
Artrite Experimental/tratamento farmacológico , Inibidores das Enzimas do Citocromo P-450/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Glucocorticoides/metabolismo , Tiadiazóis/farmacologia , Animais , Sangue/efeitos dos fármacos , Sangue/metabolismo , Técnicas de Química Sintética , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Masculino , Ratos Endogâmicos Lew , Receptores de Glucocorticoides/agonistas , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacocinética , Fator de Transcrição AP-1/metabolismo
13.
J Pharm Sci ; 104(4): 1522-32, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25641187

RESUMO

ARRY-403 is a glucokinase activator developed for the treatment of diabetes. Less than dose-proportional exposure was observed during single ascending dose studies with ARRY-403. A physiologically based pharmacokinetic (PBPK) model for ARRY-403 was developed through integration of in vitro physicochemical data with precipitation time estimations based on results from the single ascending dose studies; PBPK modeling indicated that the primary cause of the less than dose-proportional exposure was dose-limited absorption because of pH-dependent solubility. The impact of dose, particle size, and fasted or fed state on ARRY-403 exposure was examined through sensitivity analyses and used to refine the PBPK model. On the basis of the marked pH-dependent solubility of ARRY-403, the refined PBPK model was used to simulate the effects of acid-reducing agents (ARAs) on ARRY-403 exposure, as these agents are widely available and could be coadministered with ARRY-403. The simulations indicated that a clinical study with an ARA was warranted; in a clinical study, famotidine had a marked effect on ARRY-403 exposure. This approach, based on the "predict, learn, and confirm" paradigm, demonstrates the utility of integrating physicochemical properties, in vitro experiments, and clinical results using PBPK to inform formulation development and to guide clinical study design.


Assuntos
Aminopiridinas/farmacocinética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/farmacocinética , Glucoquinase/metabolismo , Hipoglicemiantes/farmacocinética , Modelos Biológicos , Tiadiazóis/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Aminopiridinas/administração & dosagem , Aminopiridinas/sangue , Aminopiridinas/química , Química Farmacêutica , Simulação por Computador , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/enzimologia , Interações Medicamentosas , Ativação Enzimática , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/sangue , Ativadores de Enzimas/química , Jejum/sangue , Feminino , Absorção Gastrointestinal , Humanos , Concentração de Íons de Hidrogênio , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Período Pós-Prandial , Ligação Proteica , Ensaios Clínicos Controlados Aleatórios como Assunto , Solubilidade , Tecnologia Farmacêutica/métodos , Tiadiazóis/administração & dosagem , Tiadiazóis/sangue , Tiadiazóis/química , Adulto Jovem
14.
Invest New Drugs ; 33(2): 440-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25684345

RESUMO

Purpose Filanesib (ARRY-520) is a highly selective, targeted inhibitor of kinesin spindle protein (KSP) inhibitor that induces mitotic arrest and subsequent tumor cell death. This first-in-human Phase 1 study evaluated dose-limiting toxicities (DLTs) and determined a maximum tolerated dose (MTD) for filanesib administered as a 1-h intravenous infusion on 2 treatment schedules in patients with advanced solid tumors. The pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of filanesib were also evaluated. Methods Filanesib was administered on Day 1 of each 3-week cycle (Initial Schedule) or Days 1 and 2 of each 2-week cycle (Alternate Schedule). A standard 3 + 3 dose-escalation design was employed. An expansion cohort was conducted at the MTD of the Initial Schedule. Filanesib PK was evaluated in plasma (both schedules) and urine (Initial Schedule only). Monopolar spindle formation was evaluated in biopsies taken from patients in the expansion cohort. Results Forty-one patients received filanesib. The MTD was equivalent for both the Initial and Alternate Schedules (2.50 mg/m(2)/cycle). The prevalence of neutropenia as a DLT for both schedules necessitated adding prophylactic filgrastim to another dose escalation on the Alternate Schedule (highest tolerated dose 3.20 mg/m(2)/cycle). Neurotoxicity related to filanesib was not observed. Dose-proportional increases in filanesib exposure were observed. The half-life for filanesib was ~70 h. Monopolar spindles in patient biopsy samples indicated KSP inhibition. Stable disease was the best tumor response observed in 18 % (7/39) of evaluable patients. Conclusion Filanesib provided exposures with acceptable tolerability and evidence of target-specific pharmacodynamic effects.


Assuntos
Antineoplásicos/farmacologia , Cinesina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Tiadiazóis/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Masculino , Dose Máxima Tolerável , Proteínas de Membrana , Pessoa de Meia-Idade , Tiadiazóis/administração & dosagem , Tiadiazóis/efeitos adversos , Tiadiazóis/farmacocinética
15.
Arterioscler Thromb Vasc Biol ; 34(10): 2321-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25147334

RESUMO

OBJECTIVE: Treatment of myocardial infarction within the first 1 to 2 hours with a thrombolytic agent, percutaneous coronary intervention, or an αIIbß3 antagonist decreases mortality and the later development of heart failure. We previously reported on a novel small molecule αIIbß3 antagonist, RUC-2, that has a unique mechanism of action. We have now developed a more potent and more soluble congener of RUC-2, RUC-4, designed to be easily administered intramuscularly by autoinjector to facilitate its use in the prehospital setting. Here, we report the properties of RUC-4 and the antiplatelet and antithrombotic effects of RUC-2 and RUC-4 in animal models. APPROACH AND RESULTS: RUC-4 was ≈ 20% more potent than RUC-2 in inhibiting human ADP-induced platelet aggregation and much more soluble in aqueous solutions (60-80 mg/mL). It shared RUC-2's specificity for αIIbß3 versus αVß3, did not prime the receptor to bind fibrinogen, or induce changes in ß3 identified by a conformation-specific monoclonal antibody. Both RUC-2 and RUC-4 prevented FeCl3-induced thrombotic occlusion of the carotid artery in mice and decreased microvascular thrombi in response to laser injury produced by human platelets infused into transgenic mice containing a mutated von Willebrand factor that reacts with human but not mouse platelets. Intramuscular injection of RUC-4 in nonhuman primates at 1.9 and 3.85 mg/kg led to complete inhibition of platelet aggregation within 15 minutes, with dose-dependent return of platelet aggregation after 4.5 to 24 hours. CONCLUSIONS: RUC-4 has favorable biochemical, pharmacokinetic, pharmacodynamic, antithrombotic, and solubility properties as a prehospital therapy of myocardial infarction, but the possibility of increased bleeding with therapeutic doses remains to be evaluated.


Assuntos
Plaquetas/efeitos dos fármacos , Estenose das Carótidas/prevenção & controle , Serviços Médicos de Emergência , Fibrinolíticos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Pirimidinonas/farmacologia , Tiadiazóis/farmacologia , Trombose/prevenção & controle , Animais , Sítios de Ligação , Plaquetas/metabolismo , Estenose das Carótidas/sangue , Estenose das Carótidas/induzido quimicamente , Cloretos , Modelos Animais de Doenças , Compostos Férricos , Fibrinolíticos/química , Fibrinolíticos/metabolismo , Fibrinolíticos/farmacocinética , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Transgênicos , Simulação de Dinâmica Molecular , Infarto do Miocárdio/sangue , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/metabolismo , Inibidores da Agregação de Plaquetas/farmacocinética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ligação Proteica , Conformação Proteica , Pirimidinonas/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacocinética , Solubilidade , Tiadiazóis/química , Tiadiazóis/metabolismo , Tiadiazóis/farmacocinética , Trombose/sangue , Trombose/induzido quimicamente , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo
16.
J Med Chem ; 57(13): 5664-78, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-24892980

RESUMO

A series of novel pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by the agar dilution method and Oxford cup assay. The majority of the tested compounds displayed moderate antibacterial activities. Importantly, the three compounds with amino or tertiary amine groups in their side chains, 11, 13b, and 15c, were the most active antibacterial agents. Docking experiments carried out on the peptidyl transferase center (PTC) of 23S rRNA proved that there is a reasonable direct correlation between the binding free energy (ΔGb, kcal/mol) and the antibacterial activity. Moreover, the pharmacokinetic profiles of 11 and 15c in rat were characterized by moderate clearance and oral bioavailability.


Assuntos
Bactérias/efeitos dos fármacos , Resistência a Meticilina/efeitos dos fármacos , Tiadiazóis/síntese química , Animais , Diterpenos/síntese química , Diterpenos/farmacocinética , Diterpenos/farmacologia , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Acoplamento Molecular , Compostos Policíclicos , Ratos , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-Atividade , Termodinâmica , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologia
17.
Cancer Chemother Pharmacol ; 74(1): 15-23, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24752449

RESUMO

PURPOSE: Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors. METHODS: LY2523355 was given on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m²/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia. RESULTS: Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m²/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100 %). Grade 4 neutropenia was observed in 83 %, but all recovered to above 500 neutrophils/µl within 7 days. All patients at 4 and 5 mg/m²/day required G-CSF support. No dose-limiting toxicities were reported up to 5 mg/m²/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed. CONCLUSIONS: The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m²/day in Japanese patients with advanced solid tumors.


Assuntos
Antineoplásicos/administração & dosagem , Drogas em Investigação/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Cinesina/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Sulfonamidas/administração & dosagem , Tiadiazóis/administração & dosagem , Adulto , Idoso , Regulação Alostérica , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Institutos de Câncer , Neutropenia Febril Induzida por Quimioterapia/fisiopatologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Relação Dose-Resposta a Droga , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Drogas em Investigação/uso terapêutico , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Feminino , Meia-Vida , Humanos , Japão , Cinesina/metabolismo , Leucopenia/induzido quimicamente , Leucopenia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Neoplasias/sangue , Neoplasias/metabolismo , Índice de Gravidade de Doença , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Tiadiazóis/efeitos adversos , Tiadiazóis/farmacocinética , Tiadiazóis/uso terapêutico
18.
J Neuroimaging ; 23(2): 219-23, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22817997

RESUMO

BACKGROUND AND PURPOSE: Aquaporin 4 (AQP-4) is the most abundant aquaporin isoform in the brain. Alterations in its expression and distribution have been correlated with the progression of several clinical disorders; however, the specific roles of AQP-4 in those disorders are not well understood. Visualizing AQP-4 in vivo is expected to provide fresh insights into its roles in disease pathology, as well as aiding the clinical assessment of those disorders. METHODS: We developed a 11C-labeled analogue of the AQP-4 ligand TGN-020 (2-nicotinamido-1,3,4-thiadiazole) suitable for in vivo positron emission tomography (PET) imaging. RESULTS: In the present study, we report the first PET images of AQP-4 in the human brain. The results unequivocally demonstrated a specific distribution pattern for AQP-4 within the brain, namely, the subpial and perivascular endfeet of astrocytes. The choroid plexus, where both AQP-4 and AQP-1 are expressed, also showed substantial uptake of the ligand. CONCLUSIONS: Based on these initial results, we believe [11C]TGN-020 PET will be valuable in determining the role of AQP-4 in disease progression, and for the clinical assessment of water homeostasis under various settings.


Assuntos
Aquaporina 4/antagonistas & inibidores , Aquaporina 4/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Niacinamida/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Tiadiazóis/farmacocinética , Adulto , Animais , Encéfalo/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Niacinamida/farmacocinética , Projetos Piloto , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/toxicidade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual
19.
J Med Chem ; 55(9): 4286-96, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-22500954

RESUMO

A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P(1) agonists. The extensive structure-activity relationship studies for these analogues were reported. Among them, 17g was identified to show high in vitro potency with reasonable free unbound fraction in plasma (F(u) > 0.5%), good brain penetration (BBR > 0.5), and desirable pharmacokinetic properties in mouse and rat. Oral administration of 1 mg/kg 17g resulted in significant peripheral lymphocytes reduction at 4 h after dose and rapid lymphocytes recovery at 24 h. 17g showed a transient lymphopenia profile in the repeated dose study in mouse. In addition, 17g also demonstrated efficacy comparable to that of FTY720 (1) in the mouse EAE model of MS.


Assuntos
Imunossupressores/síntese química , Imunossupressores/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Receptores de Lisoesfingolipídeo/agonistas , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Administração Oral , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Imunossupressores/química , Imunossupressores/farmacocinética , Contagem de Linfócitos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla Recidivante-Remitente/metabolismo , Ratos , Receptores de Lisoesfingolipídeo/metabolismo , Organismos Livres de Patógenos Específicos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacocinética
20.
Bioorg Med Chem Lett ; 22(9): 3354-7, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22464130

RESUMO

A structure-activity relationship study was undertaken to address the lack of oral exposure of the H3 antagonist 1, which incorporated an arylketone. Among a number of sub-series, the 4H-pyrido[1,2-a]pyrimidin-4-one analog 21 showed an improved PK profile in rat and mouse and was active in an obesity model. The pyrimidin-4-one proved to be a novel and useful ketone bioisostere.


Assuntos
Antagonistas dos Receptores Histamínicos H3/farmacocinética , Tiadiazóis/farmacologia , Administração Oral , Animais , Cetonas , Obesidade/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Tiadiazóis/farmacocinética
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