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1.
J Med Chem ; 63(7): 3723-3736, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32134263

RESUMO

Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.


Assuntos
Adamantano/uso terapêutico , Ácidos Carboxílicos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Esquistossomicidas/uso terapêutico , Compostos de Espiro/uso terapêutico , Adamantano/análogos & derivados , Adamantano/farmacocinética , Adamantano/toxicidade , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/toxicidade , Linhagem Celular Tumoral , Feminino , Células HEK293 , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Heterocíclicos com 1 Anel/toxicidade , Humanos , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/síntese química , Esquistossomicidas/farmacocinética , Esquistossomicidas/toxicidade , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Compostos de Espiro/toxicidade , Relação Estrutura-Atividade
2.
Heart ; 105(24): 1868-1875, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31422361

RESUMO

OBJECTIVES: Intraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αvß3) integrin pathway. We investigated the applicability of the αvß3-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis. METHODS: Vascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217-237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBRmax). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring. RESULTS: 18F-Fluciclatide uptake co-localised with regions of increased αvß3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.29 vs 1.21, p=0.02). CONCLUSIONS: In vivo expression of αvß3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αvß3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis.


Assuntos
Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/metabolismo , Aterosclerose/diagnóstico por imagem , Aterosclerose/metabolismo , Integrina alfaVbeta3/metabolismo , Idoso , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/metabolismo , Ácidos Carboxílicos/farmacocinética , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/metabolismo , Ciclobutanos/farmacocinética , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/metabolismo
3.
Radiographics ; 39(3): 822-841, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31059396

RESUMO

Fluorine 18 (18F) fluciclovine (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid [FACBC]) is a radiolabeled amino acid analog that takes advantage of the amino acid transport upregulation in several types of cancer cells. FACBC is taken up to a greater extent in prostate cancer cells than in surrounding normal tissue, providing an opportunity for its use in cases of this common cancer. In 2016, the U.S. Food and Drug Administration found the accuracy of FACBC PET to be superior to that of other molecular imaging techniques and subsequently granted approval for its use in PET of recurrent prostate cancer. As FACBC is an 18F radiotracer, an on-site cyclotron is not required for its production. This feature enables the widespread clinical availability of this agent and, in turn, an opportunity for improved patient care. The clinical pharmacology and imaging features of FACBC are reviewed, and the role of this agent in the imaging of recurrent prostate cancer, within the context of research that supports its effectiveness, is discussed. The administration of and image acquisition facilitated by using FACBC, as compared with 18F fluorodeoxyglucose, which is more widely used, are described. In addition, the criteria for interpreting FACBC imaging findings are outlined, with emphasis on common causes of false-positive and false-negative findings. ©RSNA, 2019.


Assuntos
Adenocarcinoma/secundário , Ácidos Carboxílicos , Ciclobutanos , Radioisótopos de Flúor , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Idoso , Aminoácidos/metabolismo , Transporte Biológico , Ácidos Carboxílicos/farmacocinética , Ciclobutanos/farmacocinética , Diagnóstico Diferencial , Radioisótopos de Flúor/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias/métodos , Especificidade de Órgãos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prostatectomia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Prostatite/diagnóstico por imagem , Compostos Radiofarmacêuticos/farmacocinética
4.
Mol Nutr Food Res ; 63(14): e1801341, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31125183

RESUMO

SCOPE: Coffee is a complex mixture of over 1000 compounds, including diverse heteroaromatic compounds such as alkylpyrazines. Little is known about the intake, metabolism, and bodily distribution of these compounds. Therefore, a human intervention study is conducted to investigate the excretion of alkylpyrazine metabolites in urine after the ingestion of brewed coffee containing alkylpyrazines. METHODS AND RESULTS: After consuming a diet without heat-processed food, ten volunteers consumed 500 mL of freshly brewed coffee prepared from coffee pads, providing intakes of 2-methylpyrazine (2-MeP), 2,5-dimethylpyrazine (2,5-DMeP), and 2,6-dimethylpyrazine (2,6-DMeP) amounting to 17.2, 4.4, and 4.9 µmol, respectively. These alkylpyrazines are metabolized into the corresponding pyrazine carboxylic acids, namely pyrazine-2-carboxylic acid (PA), 5-hydroxypyrazine-2-carboxylic acid (5-OHPA), 5-methylpyrazine-2-carboxylic acid (5-MePA), and 6-methylpyrazine-2-carboxylic acid (6-MePA). In total, 64% of the ingested 2-MeP is excreted as PA, as well as 26% as 5-OHPA, while 91% and 97% of the ingested 2,5-DMeP and 2,6-DMeP are recovered as 5-MePA and 6-MePA, respectively, in urine samples collected after coffee consumption. CONCLUSION: This study provides evidence that alkylpyrazines are rapidly metabolized into the corresponding carboxylic acids and excreted via urine by humans, which is consistent with earlier rodent studies.


Assuntos
Café/química , Pirazinas/farmacocinética , Adulto , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/urina , Cromatografia Líquida de Alta Pressão , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pirazinamida/análogos & derivados , Pirazinamida/farmacocinética , Pirazinas/urina , Espectrometria de Massas por Ionização por Electrospray
5.
J Med Chem ; 62(9): 4350-4369, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-30951312

RESUMO

Through a phenotypic high-throughput screen using a serum response element luciferase promoter, we identified a novel 5-aryl-1,3,4-oxadiazol-2-ylthiopropionic acid lead inhibitor of Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF)-mediated gene transcription with good potency (IC50 = 180 nM). We were able to rapidly improve the cellular potency by 5 orders of magnitude guided by sharply defined and synergistic SAR. The remarkable potency and depth of the SAR, as well as the relatively low molecular weight of the series, suggests, but does not prove, that binding to the unknown molecular target may be occurring through a covalent mechanism. The series nevertheless has no observable cytotoxicity up to 100 µM. Ensuing pharmacokinetic optimization resulted in the development of two potent and orally bioavailable anti-fibrotic agents that were capable of dose-dependently reducing connective tissue growth factor gene expression in vitro as well as significantly reducing the development of bleomycin-induced dermal fibrosis in mice in vivo.


Assuntos
Ácidos Carboxílicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Fibrose/tratamento farmacológico , Oxidiazóis/uso terapêutico , Fator de Resposta Sérica/antagonistas & inibidores , Transativadores/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacocinética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Feminino , Fibrose/patologia , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Transdução de Sinais/efeitos dos fármacos , Pele/patologia , Relação Estrutura-Atividade , Transcrição Genética/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/antagonistas & inibidores
6.
Mol Imaging Biol ; 21(5): 818-824, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30617729

RESUMO

PURPOSE: To evaluate the ability of anti-1-amino-3-anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid ([18F]fluciclovine) positron emission tomography/X-ray computed tomography (PET/CT) in comparison to Technetium-99m 2-methoxy isobutyl isonitrile ([99mTc]sestamibi) single-photon emission computed tomography/CT (SPECT/CT) for the localization of hyperfunctioning parathyroid glands in patients with hyperparathyroidism. PROCEDURES: Four patients with hyperparathyroidism underwent 60-minutes sequential neck and thorax PET/CT after [18F]fluciclovine (352 ± 28 MBq) injection. Lesion uptake and target-to-background ratios (TBR) were compared with [99mTc]sestamibi (798 ± 27 MBq) SPECT/CT in the same patient. RESULTS: Both techniques detected 4/5 hyperfunctioning parathyroid glands identified at surgery. The highest [18F]fluciclovine uptake and TBRs were at 5-9 min with rapid washout. [99mTc]sestamibi had significantly higher TBRs compared with [18F]fluciclovine (5-9 min) for blood pool (10.9 ± 4.7 vs 1.3 ± 0.6; p < 0.01) and reference muscle backgrounds (5.8 ± 3.0 vs 1.7 ± 0.6; p < 0.01), with non-significant trend for thyroid tissue background (1.3 ± 0.5 vs 1.1 ± 0.5; p = 0.73). CONCLUSION: Hyperfunctioning parathyroid glands can be detected on [18F]fluciclovine PET/CT at early imaging, but conspicuity (TBR) is better with [99mTc]sestamibi. [18F]fluciclovine PET/CT does not seem promising in the detection of hyperfunctioning parathyroid glands.


Assuntos
Ácidos Carboxílicos/química , Ciclobutanos/química , Glândulas Paratireoides/diagnóstico por imagem , Glândulas Paratireoides/fisiopatologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Ácidos Carboxílicos/farmacocinética , Ciclobutanos/farmacocinética , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tecnécio Tc 99m Sestamibi/farmacocinética
7.
Clin Pharmacol Drug Dev ; 8(4): 467-479, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29878583

RESUMO

The orally available chymase inhibitor BAY 1142524 is currently being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Results from 3 randomized, single-center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first-in-human study, single oral doses of 1-200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high-fat/high-calorie meal were investigated at the 5-mg dose. In a multiple-dose escalation study, doses of 5-50 mg twice daily and 100 mg once daily were given for 5 consecutive days. BAY 1142524 was safe and well tolerated and had no effects on heart rate or blood pressure compared with placebo. BAY 1142524 was absorbed with peak concentration 1-3 hours after administration for IR tablets; it was eliminated from plasma with a terminal half-life of 6.84-12.0 hours after administration of liquid service formulation or IR tablets. Plasma exposures appeared to be dose-linear, with a negligible food effect. There was only low accumulation of BAY 1142524 after multiple dosing. BAY 1142524 exhibited a pharmacokinetic profile allowing for once-daily dosing. The absence of blood pressure effects after administration of BAY 1142524 supports the combination of this novel anti-remodeling drug with existing standard of care in patients with left-ventricular dysfunction after acute myocardial infarction.


Assuntos
Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/farmacocinética , Quimases/antagonistas & inibidores , Jejum/sangue , Indenos/administração & dosagem , Indenos/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Disponibilidade Biológica , Ácidos Carboxílicos/efeitos adversos , Preparações de Ação Retardada , Esquema de Medicação , Meia-Vida , Voluntários Saudáveis , Humanos , Indenos/efeitos adversos , Masculino , Pirimidinas/efeitos adversos , Soluções , Comprimidos , Adulto Jovem
8.
Clin Pharmacol Drug Dev ; 8(5): 612-618, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30556959

RESUMO

This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of miridesap (GSK2315698) following an intravenous (IV) infusion in healthy Japanese men. Subjects in Cohort 1 received 1-hour IV infusions of 10, 20, and 40 mg of miridesap or placebo, and subjects in Cohort 2 received a 15-hour IV infusion of 20 mg/h of miridesap or placebo. No treatment-related adverse events were reported. No new safety signals were identified for either vital signs or clinical laboratory parameters. A dose-dependent increase was observed in miridesap exposure (area under the concentration-time curve and maximum observed drug concentration) in the 10 to 40 mg/h dose range after a 1-hour IV infusion of miridesap. Rapid depletion of circulating serum amyloid P component was observed after the initiation of miridesap infusion. Serum amyloid P component concentrations fell in a dose-dependent manner following administration of miridesap.


Assuntos
Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Componente Amiloide P Sérico/análise , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/farmacocinética , Adulto , Área Sob a Curva , Ácidos Carboxílicos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Japão , Ligantes , Masculino , Pessoa de Meia-Idade , Pirrolidinas/efeitos adversos , Componente Amiloide P Sérico/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/efeitos adversos , Fatores de Tempo , Adulto Jovem
9.
Clin Pharmacol Drug Dev ; 8(7): 942-951, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30452784

RESUMO

The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose. Patients were treated for 2 weeks with either placebo (n = 12) or 4 different doses of fulacimstat (5 mg twice daily, n = 9; 10 mg twice daily, n = 9; 25 mg twice daily, n = 10; 50 mg once daily, n = 9). Fulacimstat was safe and well tolerated at all examined doses. There were no clinically relevant effects on vital signs or potassium levels compared with placebo treatment. Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Ácidos Carboxílicos/administração & dosagem , Insuficiência Cardíaca/prevenção & controle , Indenos/administração & dosagem , Infarto do Miocárdio/complicações , Pirimidinas/administração & dosagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Adulto , Idoso , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/farmacocinética , Quimases/antagonistas & inibidores , Esquema de Medicação , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Indenos/efeitos adversos , Indenos/farmacocinética , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Resultado do Tratamento , Disfunção Ventricular Esquerda/etiologia
10.
Yakugaku Zasshi ; 138(9): 1163-1167, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30175760

RESUMO

 For efficient and deeper drug delivery into the lungs via dry powder inhalers (DPIs), we designed porous spray-dried particles (SDPs) containing anti-tuberculosis drugs and sugar-based excipients. The SDPs were prepared by spray-drying ethanol solutions containing isoniazid and/or rifampicin and sucrose, maltose, or highly branched cyclic dextrin (HBCD). Solid-state fluorescence emission spectroscopy showed that 1-naphthoic acid (1-NPA), a model drug, was dispersed in a molecular dispersion/solid solution, suggesting high potential of HBCD as an excipient in DPIs. 1-NPA was dispersed not only as active pharmaceutical ingredient (API) molecules with HBCD, but also as fine crystals. Morphological examination showed that the fine particles of HBCD/anti-tuberculosis drugs were porous, indicating high aerodynamic performance. Isoniazid and rifampicin could also be incorporated into the HBCD matrix. HBCD formulations exhibited higher released doses and fine-particle fractions than sucrose and maltose formulations, and could incorporate both hydrophilic and hydrophobic drugs.


Assuntos
Antituberculosos/administração & dosagem , Dextrinas , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Inaladores de Pó Seco , Excipientes , Isoniazida/administração & dosagem , Maltose , Rifampina/administração & dosagem , Sacarose , Administração por Inalação , Antituberculosos/farmacocinética , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/farmacocinética , Etanol , Humanos , Interações Hidrofóbicas e Hidrofílicas , Isoniazida/farmacocinética , Naftalenos/administração & dosagem , Naftalenos/farmacocinética , Tamanho da Partícula , Porosidade , Pós , Rifampina/farmacocinética , Soluções
11.
PLoS One ; 13(8): e0201367, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30071037

RESUMO

AIM: The aim of this study was to compare the plasma exposure and tissue accretion of docosahexaenoic acid (DHA) in response to oral dosing of free carboxylic acid (OM3CA) and ethyl ester (OM3EE) forms. MATERIALS AND METHODS: Sixteen adult male Wistar rats, fed a low-fat, carbohydrate-rich, standard chow diet, were chronically catheterized and gavaged for 5 consecutive days with either OM3CA (n = 9) or OM3EE (n = 7), the last day fasted overnight and spiked respectively with either 14C-DHA or 14C-DHA-ethyl ester (14C-DHA-EE) tracers. Appearance of 14C-labelled plasma polar and neutral lipids over 4 h and retention of 14C-activity (R) in the tissues at 4 h were measured. RESULTS: Compared to OM3EE, OM3CA resulted in 2- and 3-fold higher areas under the plasma 14C-labelled polar and neutral lipid curves (exposures), respectively, as well as, higher R in all tissues examined. For both OM3CA and OM3EE, R varied in a tissue specific manner; highest in liver, followed by red skeletal muscle, adipose tissue, brain and white skeletal muscle. Multiple linear regression analysis revealed that R in each tissue (except liver) was dependent on polar lipid exposure alone (r2>0.87 and P<0.001), but not neutral lipid exposure, and furthermore this dependence was indistinguishable for OM3CA and OM3EE. In the liver, R was found to be dependent on both polar and neutral lipid exposures (r2 = 0.97, P<0.001), with relative contributions of 85±2% and 15±2%, respectively. As for the other tissues, these dependencies were indistinguishable for OM3CA and OM3EE. CONCLUSION: The present results, in fasted low-fat diet fed rats, are consistent with higher oral bioavailability of OM3CA versus OM3EE forms of DHA. Once DHA has entered the circulation, the tissue distribution is independent of the dosed form and uptake in the skeletal muscle, fat and brain is driven by the polar pools of DHA in plasma, while DHA accretion in liver is supplied by both polar and neutral plasma lipids.


Assuntos
Ácidos Carboxílicos , Carboidratos da Dieta/farmacologia , Ácidos Docosa-Hexaenoicos , Animais , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/farmacologia , Ácidos Docosa-Hexaenoicos/farmacocinética , Ácidos Docosa-Hexaenoicos/farmacologia , Masculino , Especificidade de Órgãos , Ratos , Ratos Wistar
12.
Toxicol Sci ; 166(1): 123-130, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30060248

RESUMO

CKA, a chemokine receptor antagonist intended for treating inflammatory conditions, produced dose-dependent hepatotoxicity in rats but advanced into the clinic where single doses of CKA up to 600 mg appeared safe in humans. Because existing toxicological platforms used during drug development are not perfectly predictive, a quantitative systems toxicology model investigated the hepatotoxic potential of CKA in humans and rats through in vitro assessments of CKA on mitochondrial respiration, oxidative stress, and bile acid transporters. DILIsym predicted that single doses of CKA caused serum ALT >3xULN in a subset of the simulated rat population, while single doses in a simulated human population did not produce serum ALT elevations. Species differences were largely attributed to differences in liver exposure, but increased sensitivity to inhibition of mitochondrial respiration in the rat also contributed. We conclude that mechanistic modeling can elucidate species differences in the hepatotoxic potential of drug candidates.


Assuntos
Ácidos Carboxílicos/toxicidade , Proteínas de Transporte/antagonistas & inibidores , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Indóis/toxicidade , Glicoproteínas de Membrana/antagonistas & inibidores , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Receptores de Quimiocinas/antagonistas & inibidores , Adulto , Animais , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Células Hep G2 , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Ratos Wistar , Especificidade da Espécie , Distribuição Tecidual
13.
J Nucl Med ; 59(2): 327-333, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28864634

RESUMO

The lysophosphatidic acid receptor type 1 (LPA1) is 1 of 6 known receptors of the extracellular signaling molecule lysophosphatidic acid. It mediates effects such as cell proliferation, migration, and differentiation. In the lung, LPA1 is involved in pathways leading, after lung tissue injury, to pulmonary fibrosis instead of normal healing, by mediating fibroblast recruitment and vascular leakage. Thus, a LPA1 PET radiotracer may be useful for studying lung fibrosis or for developing LPA1-targeting drugs. We developed and evaluated the radiotracer 11C-BMT-136088 (1-(4'-(3-methyl-4-(((1(R)-(3-11C-methylphenyl)ethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid) in rhesus monkeys to image LPA1 in the lung in vivo with PET. Methods: The study consisted of 3 parts: test-retest scans; self-saturation to estimate the tracer's in vivo dissociation constant, nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND); and dosimetry. In the first 2 parts, the radiotracer was administered using a bolus-plus-infusion protocol, the arterial input function was measured, and the animals underwent 2 scans per day separated by about 4 h. Lung regions of interest were segmented, and the tissue density estimated, from CT images. A fixed blood volume correction was applied. The tracer volume of distribution (VT) was estimated using multilinear analysis 1 (MA1) or equilibrium analysis (EA). Results:11C-BMT-136088 baseline VT was 1.83 ± 0.16 (MA1, n = 5) or 2.1 ± 0.55 (EA, n = 7) mL of plasma per gram of tissue in the left and right lung regions of interest, with a test-retest variability of -6% (MA1, n = 1) or -1% ± 14% (EA, n = 2). For the self-saturation study, 11C-BMT-136088 VND and BPND were estimated to be 0.9 ± 0.08 mL of plasma per gram of tissue and 1.1 ± 0.14, respectively. The unlabeled drug dose and plasma concentration leading to a 50% reduction of 11C-BMT-136088 specific binding were 73 ± 30 nmol/kg and 28 ± 12 nM, respectively. The average plasma free fraction was 0.2%; thus, the tracer's in vivo dissociation constant was estimated to be 55 pM. For the dosimetry study, the highest organ dose was in the liver (43.1 ± 4.9 and 68.9 ± 9.4 µSv/MBq in reference human male and female phantoms, respectively), and the effective dose equivalent was 6.9 ± 0.6 and 8.7 ± 0.6 µSv/MBq, respectively. Conclusion: Specific binding of 11C-BMT-136088 can be reliably measured to quantify LPA1 in the lungs of rhesus monkeys in vivo.


Assuntos
Radioisótopos de Carbono/metabolismo , Ácidos Carboxílicos/metabolismo , Pulmão/diagnóstico por imagem , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Feminino , Processamento de Imagem Assistida por Computador , Cinética , Ligantes , Pulmão/metabolismo , Macaca mulatta , Masculino , Tomografia por Emissão de Pósitrons , Radioquímica , Radiometria , Distribuição Tecidual
14.
Clin Pharmacol Drug Dev ; 7(2): 177-187, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28597973

RESUMO

OM3-CA (omega-3-carboxylic acids) is a complex mixture of omega-3 carboxylic acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which is approved in the United States for the treatment of hypertriglyceridemia. As part of its clinical development in Japan, we performed a phase 1 study to investigate the safety, tolerability, and pharmacokinetics after single and multiple doses of OM3-CA in healthy male Japanese subjects. Eighteen Japanese subjects were allocated to receive 2 or 4 g/day OM3-CA, or placebo (n = 6 per group). In addition, 6 white subjects received 4 g/day OM3-CA. The primary objective was to determine the safety and tolerability of OM3-CA. Plasma concentrations of EPA and DHA were adjusted for baseline values for pharmacokinetic analysis. Overall, OM3-CA was well tolerated in healthy Japanese subjects. Two Japanese subjects in each group and 5 white subjects experienced adverse events (AEs). Alanine aminotransferase increase was the most common AE in Japanese subjects, also seen with placebo, and diarrhea was the most common AE in white subjects. The maximum plasma concentrations of EPA and DHA were observed 5-6 hours postdose. The pharmacokinetic profiles of EPA and DHA after administration of OM3-CA were comparable between Japanese and white subjects.


Assuntos
Ácidos Carboxílicos/farmacocinética , Adulto , Grupo com Ancestrais do Continente Asiático , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/efeitos adversos , Grupo com Ancestrais do Continente Europeu , Voluntários Saudáveis , Humanos , Lipídeos/sangue , Masculino , Método Simples-Cego , Adulto Jovem
15.
J Control Release ; 262: 10-17, 2017 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-28710004

RESUMO

In this study, we aimed to develop a polyethylene glycol (PEG)-conjugated third generation polyamidoamine (PAMAM) dendrimer with multiple carboxylic acids as a bone-targeting carrier for the treatment of bone diseases. We conjugated PAMAM backbones to various carboxylic acids [aspartic acid (Asp), glutamic acid (Glu), succinic acid (Suc), or aconitic acid (Aco)] to obtain four different types of carboxylic acid-modified PAMAMs. PEG was covalently bound to carboxylic acid-modified PAMAMs to obtain PEGylated carboxylic acid-modified PAMAMs. In a tissue distribution study, the amount of 111In-labeled unmodified PAMAM taken up by the bone after intravenous injection in mice was 11.3%. In contrast, the dose of 111In-labeled PEG(5)-Asp-PAMAM, PEG(5)-Glu-PAMAM, PEG(5)-Suc-PAMAM, or PEG(5)-Aco-PAMAM that accumulated in the bone after injection was approximately 46.0, 15.6, 22.6, and 24.5%, respectively. The bone clearance rates of 111In-labeled PEGylated carboxylic acid-modified PAMAMs were proportional to their affinities to hydroxyapatite and Ca2+. An intra-bone distribution study showed that fluorescein isothiocyanate-labeled PEG(5)-Asp-PAMAM predominantly accumulated on eroded and quiescent surfaces, a pattern associated with the pathogenesis of bone diseases, such as rheumatoid arthritis and osteoporosis. Our findings indicate that PEG(5)-Asp-PAMAM is a promising drug carrier for efficient drug targeting to the bones.


Assuntos
Osso e Ossos/metabolismo , Ácidos Carboxílicos/administração & dosagem , Dendrímeros/administração & dosagem , Portadores de Fármacos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Doenças Ósseas/tratamento farmacológico , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/uso terapêutico , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/uso terapêutico , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapêutico , Masculino , Camundongos , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/uso terapêutico
16.
J Clin Lipidol ; 11(3): 739-748, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28506390

RESUMO

BACKGROUND: Omega-3 carboxylic acids (OM3-CA) can lower triglyceride levels. OM3-CA is often prescribed concomitantly with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin). OBJECTIVE: The aim of the article was to assess the potential for pharmacokinetic interaction between OM3-CA and the statins rosuvastatin and simvastatin. METHODS: Data from 2 phase I studies (ECLIPSE III and OM-EPA-007 [NCT01486433]) were analyzed. In ECLIPSE III, 59 participants received OM3-CA 4 g once daily for 13 days, with rosuvastatin 40 mg (single dose) co-administered with the 11th dose. In OM-EPA-007, 52 participants received simvastatin 40 mg plus acetylsalicylic acid 81 mg daily for 14 days, with or without OM3-CA. Lack of a drug-drug interaction was declared if the 90% confidence interval (CI) of the geometric least-squares mean ratio of pharmacokinetic parameters was in the range 80% to 125%. RESULTS: For rosuvastatin, values for the geometric mean ratio (90% CI) with:without OM3-CA were 86.38% (80.68-92.48), 90.50% (85.99-95.25), and 89.01% (84.30-93.98), respectively, for maximum plasma concentration (Cmax), area under the concentration-time curve up to last measurable concentration (AUC0-t) and extrapolated to infinity (AUC0-inf). Co-administration with a single dose of rosuvastatin did not affect the multiple-dose pharmacokinetics of constituent OM3-CA fatty acids eicosapentaenoic acid and docosahexaenoic acid. For simvastatin, values for steady state geometric mean ratio (90% CI) with:without OM3-CA were 91.61% (82.82-101.33) and 87.47% (80.19-95.41), respectively, for Cmax and AUC0-t. No deaths or serious adverse events occurred in either trial. CONCLUSION: OM3-CA can be administered with either rosuvastatin or simvastatin without affecting the pharmacokinetics of these statins.


Assuntos
Ácidos Carboxílicos/farmacocinética , Voluntários Saudáveis , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Sinvastatina/farmacocinética , Adolescente , Adulto , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/química , Interações Medicamentosas , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Rosuvastatina Cálcica/efeitos adversos , Segurança , Sinvastatina/efeitos adversos , Adulto Jovem
17.
Steroids ; 124: 29-34, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28549802

RESUMO

5α-Reductase is a key enzyme responsible for dihydrotestosterone biosynthesis and has been recognized as an important target for discovering new drugs against benign prostatic hyperplasia (BPH). In this study, a series of novel steroidal androst-3,5-diene-3-carboxylic acids have been designed and synthesized. Biological evaluations were performed on their 5α-reductase inhibitory activities by both in vitro enzyme inhibition assay and in vivo by prostate weighing method. Results showed that most of them displayed excellent 5α-reductase inhibitory potency. Detailed evaluation indicated that most of the compounds displayed slightly higher inhibition potency towards type 2 isozyme. Among all the compounds, 16a was found to be the most potential inhibitor with the IC50 of 0.25µM and 0.13µM against type 1 and 2 isozymes respectively. In vivo 5a-reductase inhibitory evaluation of 16a also showed a more significant reduction effect (p<0.001) in rat prostate weight than epristeride. Furthermore, the results of in silico ADME study indicated that compound 16a exhibited good pharmacokinetic properties. Thus, 16a could serve as promising lead candidates for further study.


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Colestenona 5 alfa-Redutase/metabolismo , Desenho de Fármacos , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacocinética , Animais , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Técnicas de Química Sintética , Simulação por Computador , Masculino , Ratos
18.
J Med Chem ; 60(7): 3187-3197, 2017 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-28374589

RESUMO

GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.


Assuntos
Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Indazóis/química , Indazóis/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/análise , Ácidos Carboxílicos/farmacocinética , Humanos , Indazóis/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares
19.
J Atheroscler Thromb ; 24(9): 980-987, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28344197

RESUMO

AIMS: Omega-3-carboxylic acids (OM3-CA) contain omega-3 free fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as carboxylic acids. Food intake is known to affect the bioavailability of ethyl ester fatty acid formulations. We conducted a phase I study to investigate the effects of the timing of OM3-CA administration relative to food intake on the pharmacokinetics of EPA and DHA. METHODS: In this randomized, open-label, three-period crossover study, Japanese healthy male subjects were administered 4×1 g OM3-CA capsules with continued fasting, before a meal, or after a meal. All subjects fasted for ≥10 h prior to drug/meal administration. The primary objective was to examine the effect of meal timing on the pharmacokinetics of EPA and DHA after OM3-CA administration. The secondary objectives were to examine the safety and tolerability of OM3-CA. RESULTS: A total of 42 Japanese subjects was enrolled in the study. The baseline-adjusted maximum concentration and area under the concentration-time curve from 0 to 72 h for EPA, DHA, and EPA +DHA were lower in the fasting and before meal conditions than in the after meal condition. The maximum total EPA, total DHA, and total EPA+DHA concentrations were reached later when administered in fasting conditions than in fed conditions, indicating slower absorption in fasting conditions. Diarrhea was reported by five, six, and no subjects in the fasting, before meal, and after meal conditions, respectively. CONCLUSIONS: The timing of OM3-CA administration relative to food intake influences the systemic bioavailability of EPA and DHA in healthy Japanese male subjects. TRIAL REGISTRATION: NCT02372344.


Assuntos
Suplementos Nutricionais , Ingestão de Alimentos , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/farmacocinética , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Disponibilidade Biológica , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/sangue , Ácidos Carboxílicos/farmacocinética , Estudos Cross-Over , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/farmacocinética , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/sangue , Ácido Eicosapentaenoico/farmacocinética , Jejum/sangue , Ácidos Graxos Ômega-3/sangue , Voluntários Saudáveis , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
20.
Bioorg Med Chem Lett ; 27(8): 1627-1632, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28285913

RESUMO

The development of prodrugs has progressed with the aim of improving drug bioavailability by overcoming various barriers that reduce drug benefits in clinical use, such as stability, duration, water solubility, side effect profile, and taste. Many conventional drugs act as the precursors of an active agent in vivo; for example, the anti-HIV agent azidothymidine (AZT) is converted into its corresponding active triphosphate ester in the body, meaning that AZT is a prodrug in the broadest sense. However prodrug design is generally difficult owing to the lack of general versatility. Thus, these prodrugs, broadly defined, are often discovered by chance or trial-and-error. Recently, many prodrugs that could release the corresponding parent drugs with or without enzymatic action under physiological conditions have been reported. These prodrugs can be easily designed and synthesized because of their generally applicable modifications. This digest paper provides an overview of recent development in prodrug strategies for drugs with a carboxylic acid or hydroxyl/amino group on the basis of a generally applicable modification strategy, such as esterification, amidation, or benzylation.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Desenho de Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Amidas/química , Amidas/metabolismo , Amidas/farmacocinética , Animais , Fármacos Anti-HIV/metabolismo , Compostos de Benzil/química , Compostos de Benzil/metabolismo , Compostos de Benzil/farmacocinética , Disponibilidade Biológica , Ácidos Carboxílicos/química , Ácidos Carboxílicos/metabolismo , Ácidos Carboxílicos/farmacocinética , Esterificação , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Pró-Fármacos/metabolismo , Solubilidade , Zidovudina/análogos & derivados , Zidovudina/metabolismo , Zidovudina/farmacocinética
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