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1.
Biol Pharm Bull ; 42(6): 873-876, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155586

RESUMO

To establish a synthetic route to d3-poziotinib hydrochloride. Treatment of 4-chloro-7-hydroxyquinazolin-6-yl pivalate (1) with d3-methyliodide afforded the etherization product, which reacted with 3,4-dichloro-2-fluoroaniline to generate the key intermediate d3-4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl pivalate (3). Followed the de-protection reaction, the nucleophilic substitution (SN2) reaction with tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (TSP), and the de-protection reaction of t-butoxycarbonyl (Boc) group, and the amide formation reaction with acrylyl chloride, d3-poziotinib was obtained, which was converted to hydrochloride salt by treatment with concentrated hydrochloric acid (HCl). Starting from a known compound 4-chloro-7-hydroxyquinazolin-6-yl pivalate (1), after 7 steps transformation, d3-poziotinib hydrochloride was obtained with a total yield of 9.02%. The structure of d3-poziotinib hydrochloride was confirmed by 1H-NMR, 13C-NMR, and high resolution (HR)-MS. Meanwhile, the in vitro microsomal stability experiment showed that d3-poziotinib had a longer half time (t1/2 = 4.6 h) than poziotinib (t1/2 = 3.5 h).


Assuntos
Antineoplásicos , Deutério , Quinazolinas , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Deutério/química , Deutério/farmacocinética , Desenho de Drogas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Quinazolinas/química , Quinazolinas/farmacocinética , Ratos
2.
Eur J Pharm Sci ; 136: 104943, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31152772

RESUMO

Drug-eluting Embolic Bead - Transarterial Chemoembolisation (DEB-TACE) is a minimally invasive embolising treatment for liver tumours that allows local release of chemotherapeutic drugs via ion exchange, following delivery into hepatic arterial vasculature. Thus far, no single in vitro model has been able to accurately predict the complete kinetics of drug release from DEB, due to heterogeneity of rate-controlling mechanisms throughout the process of DEB delivery. In this study, we describe two in vitro models capable of distinguishing between early phase and late phase drug release by mimicking in vivo features of each phase. First, a vascular flow system (VFS) was used to simulate the early phase by delivering DEB into a silicon vascular cast under high pulsatile flow. This yielded a burst release profile of drugs from DEB which related to the dose adjusted Cmax observed in pharmacokinetic plasma profiles from a preclinical swine model. Second, an open loop flow-through cell system was used to model late phase drug release by packing beads in a column with an ultra-low flow rate. DEB loaded with doxorubicin, irinotecan and vandetanib showed differential drug release rates due to their varying chemical properties and unique drug-bead interactions. Using more representative in vitro models to map discrete phases of DEB drug release will provide a better capability to predict the pharmacokinetics of developmental formulations, which has implications for treatment safety and efficacy.


Assuntos
Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos/fisiologia , Irinotecano/farmacocinética , Piperidinas/farmacocinética , Quinazolinas/farmacocinética , Animais , Quimioembolização Terapêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Técnicas In Vitro , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Suínos
3.
Curr Drug Metab ; 20(7): 601-608, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237202

RESUMO

BACKGROUND: Hepatic Arterial Infusion (HAI) with raltitrexed has become an effective treatment for hepatocellular cancer and colorectal cancer liver metastases. However, traditional Body Surface Area (BSA)-based dosing is unsafe or ineffective, and a more accurate model-based approach is required. METHODS: In this study, domestic swine were given 1 mg or 4 mg raltitrexed administered by an HAI with infusion times of 30, 60 and 120 min. Hepatic Artery (HA) and Peripheral Vein (PV) samples were collected, and a twocompartment model with an elimination pathway was established to describe the in vivo behavior of raltitrexed. RESULTS: The clearance was 0.27 L/min, and the volumes of distribution were 0.35 and 6.65 L for the HA and PV compartments, respectively. The goodness-of-fit plots and visual predictive checks suggested that the proposed pharmacokinetic model agreed well with the observations. CONCLUSION: The pharmacokinetic model could be helpful in quantitatively describing the detailed processes of raltitrexed activity administered by HAI and determining an appropriate dosing regimen for preclinical and clinical studies.


Assuntos
Artéria Hepática/efeitos dos fármacos , Artéria Hepática/metabolismo , Quinazolinas/administração & dosagem , Quinazolinas/farmacocinética , Tiofenos/administração & dosagem , Tiofenos/farmacocinética , Animais , Feminino , Masculino , Suínos
4.
Nanoscale ; 11(11): 5005-5013, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30839969

RESUMO

It is acknowledged that the targeting ability of multivalent ligand-modified nanoparticles (MLNs) strongly depends on the ligand spatial presentation determined by ligand valency. However, the receptor overexpression level varies between different types or stages of tumors. Thus, it is essential to explore the influence of ligand valency on the targeting ability of MLNs to tumors with different levels of receptor overexpression. In this study, a dual-acting agent raltitrexed was used as a ligand to target the folate receptor (FR). Different copies of the raltitrexed-modified multivalent dendritic polyethyleneimine ligand cluster PRn (n = 2, 4, and 8) were conjugated onto magnetic nanoparticles to form multivalent magnetic NPs (MMNs) with different valences. The in vitro studies demonstrated that Fe-PR4 was the most effective valency in the treatment of high FR overexpressing KB cells with a decentralized receptor distribution, owing to the fact that Fe-PR2 was negative in statistical rebinding and Fe-PR8 could induce steric hindrance in the limited binding area. Instead, in moderate FR overexpressing HeLa cells with clustered receptor display, the extra ligands on Fe-PR8 would facilitate statistical rebinding more beneficially. Furthermore, in in vivo tumor inhibition and targeted magnetic resonance imaging (MRI) of KB tumors and another moderate FR expressing H22 tumor, similar results were obtained with the cell experiments. Overall, the optimizable treatment effect of Fe-PRn by modulating the ligand valency based on the overexpressing tumor receptor distribution behavior supports the potential of Fe-PRn as a nanomedicine for personalized theranostics.


Assuntos
Meios de Contraste/química , Portadores de Fármacos/química , Receptores de Folato com Âncoras de GPI/metabolismo , Nanopartículas de Magnetita/química , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Endocitose , Receptores de Folato com Âncoras de GPI/genética , Expressão Gênica , Humanos , Imagem por Ressonância Magnética , Camundongos , Neoplasias/tratamento farmacológico , Polietilenoimina/química , Quinazolinas/administração & dosagem , Quinazolinas/química , Quinazolinas/farmacocinética , Tiofenos/administração & dosagem , Tiofenos/química , Tiofenos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Ethnopharmacol ; 236: 288-301, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30872168

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Aerial parts of Peganum harmala Linn are a Uighur traditional medicinal herb in China used to treat amnesia, bronchial asthma, and cough. Deoxyvasicine (DVAS), a potent cholinesterase inhibitor exhibiting anti-senile dementia activity, is one of the chief active ingredients in aerial parts of P. harmala and plays a key role in mediating the pharmacological effects of P. harmala. However, the metabolic profiling and in vivo pharmacokinetic characteristics of DVAS still remain unknown. AIM OF THE STUDY: The aim of this present study was to investigate the metabolism and pharmacokinetic properties of DVAS in rats by using ultra-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-QTOF-MS) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-ESI-MS/MS) method. MATERIALS AND METHODS: The metabolic profiling of DVAS was evaluated in vitro and in vivo by rat liver microsomes (RLMs) incubation and by rat bio-specimens, such as urine, feces, plasma, and bile, after the oral administration of 45 mg/kg DVAS. An efficient and sensitive UPLC-ESI-MS/MS method was developed and validated to simultaneously determine DVAS and its major four metabolites, namely, vasicine, deoxyvasicinone, vasicinone, and 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-3-ß-D-glucuronide in rat plasma. For pharmacokinetic studies, 32 Sprague-Dawley rats were randomly divided into four groups, namely, intravenous dosage group (2 mg/kg DVAS) and three oral dosage groups (5, 15, and 45 mg/kg DVAS). In addition, the activity of the components in plasma after intravenous administration of DVAS was evaluated by in vitro anti-butyrylcholinesterase (BChE) assays. RESULTS: A total of 23 metabolites were found in RLMs, plasma, urine, feces, and bile by UPLC-ESI-QTOF-MS. The metabolic pathway of DVAS in vivo and in vitro mainly involved hydroxylation, dehydrogenation, acetylation, methylation, glucuronidation, and O-sulphate conjugation, and the C-3 and C-9 sites were the main metabolic soft spots. All 23 metabolites were detected in the urine sample, and 13, 8, 22, and 6 metabolites were identified from rat feces, plasma, bile, and RLMs, respectively. The standard curves of DVAS and four metabolites in rat plasma showed good linearity in the concentration range of 0.82-524.00 ng/mL with acceptable selectivity, precision, accuracy, recovery, and stability. DVAS exhibited linear dose-proportional pharmacokinetics at doses of 5, 15, and 45 mg/kg after oral administration, and the average oral absolute bioavailability of DVAS was 47.46%. The in vitro anti-BChE assays implied that the inhibitive activities were mainly due to the different concentrations of prototype DVAS. CONCLUSIONS: DVAS can be rapidly absorbed and excreted by blood, and it is also extensively metabolized in vivo, and the anti-BChE activity in blood is mainly attributed to DVAS. These findings can lay a foundation for new drug development for DVAS.


Assuntos
Alcaloides/farmacocinética , Inibidores da Colinesterase/farmacocinética , Peganum/química , Quinazolinas/farmacocinética , Administração Intravenosa , Administração Oral , Alcaloides/administração & dosagem , Alcaloides/sangue , Alcaloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/sangue , Inibidores da Colinesterase/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Ensaios Enzimáticos , Feminino , Masculino , Medicina Tradicional , Microssomos Hepáticos , Componentes Aéreos da Planta/química , Quinazolinas/administração & dosagem , Quinazolinas/sangue , Quinazolinas/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
6.
Drug Discov Today ; 24(5): 1067-1073, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30710641

RESUMO

Due to the blood-brain barrier (BBB) limiting the exposure of therapeutics to the central nervous system (CNS), patients with brain malignancies are challenging to treat, typically have poor prognoses, and represent a significant unmet medical need. Preclinical data report osimertinib to have significant BBB penetration and emerging clinical data demonstrate encouraging activity against CNS malignancies. Here, we discuss the oncology drug candidates AZD3759 and AZD1390 as case examples of discovery projects designing in BBB penetrance. We demonstrate how these innovative kinase inhibitors were recognized as brain penetrant and outline our view of experimental approaches and strategies that can facilitate the discovery of new brain-penetrant therapies for the treatment of primary and secondary CNS malignancies as well as other CNS disorders.


Assuntos
Acrilamidas/farmacocinética , Compostos de Anilina/farmacocinética , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Descoberta de Drogas , Humanos , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/farmacocinética , Quinazolinas/uso terapêutico
7.
Biomed Chromatogr ; 33(4): e4460, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30536684

RESUMO

A sensitive, selective and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of copanlisib in mouse plasma using enasidenib as an internal standard (IS) as per regulatory guideline. Copanlisib and the IS were extracted from mouse plasma using ethyl acetate as an extraction solvent and chromatographed using an isocratic mobile phase (0.2% formic acid-acetonitrile; 25:75, v/v) on a HyPURITY C18 column. Copanlisib and the IS eluted at ~0.95 and 2.00 min, respectively. The MS/MS ion transitions monitored were m/z 481.1 → 360.1 and m/z 474.0 → 456.0 for copanlisib and the IS, respectively. The calibration range was 3.59-3588 ng/mL. The intra- and inter-batch accuracy and precision (RE and RSD) across quality controls met the acceptance criteria. Stability studies showed that copanlisib was stable in mouse plasma for one month. This novel method has been applied to a pharmacokinetic study in mice.


Assuntos
Cromatografia Líquida/métodos , Pirimidinas/sangue , Pirimidinas/farmacocinética , Quinazolinas/sangue , Quinazolinas/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pirimidinas/química , Quinazolinas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos
8.
ACS Appl Mater Interfaces ; 11(1): 176-186, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30525386

RESUMO

The blood-brain tumor barrier (BTB) and blood-brain barrier (BBB) have always been the major barriers in glioma therapy. In this report, we proposed D-T7 peptide-modified nanoparticles actively targeted glioma by overcoming the BBB and BTB to improve the antiglioma efficacy. Glioma-targeting experiments showed that the penetration effect of the D-T7 peptide-modified nanoparticles was 7.89-fold higher than that of unmodified nanoparticles. Furthermore, cediranib (CD) and paclitaxel (PTX) were used for the combination of the antiangiogenesis and chemotherapy for glioma. PEGylated bilirubin nanoparticles (BRNPs) were selected as a suitable drug delivery system (CD&PTX@TBRBPs) owing to the antioxidant, anti-inflammatory, and reactive oxygen species-responsive ability. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis assays showed that CD&PTX@TBRBPs had the highest cytotoxicity and the median survival time of the CD&PTX@TBRNP group was 3.31-fold and 1.23-fold longer than that of the saline and CD&PTX@BRNP groups, respectively. All the results showed that we constructed a novel and accessible peptide-modified dual drug carrier with an enhanced antiglioma effect.


Assuntos
Bilirrubina , Neoplasias Encefálicas , Colágeno Tipo IV , Portadores de Fármacos , Glioma , Nanopartículas , Paclitaxel , Fragmentos de Peptídeos , Quinazolinas , Animais , Bilirrubina/química , Bilirrubina/farmacologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Colágeno Tipo IV/química , Colágeno Tipo IV/farmacocinética , Colágeno Tipo IV/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/farmacologia , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia
9.
J Dermatolog Treat ; 30(5): 466-470, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30265585

RESUMO

Background: A novel topical phosphodiesterase-4 inhibitor E6005 shows potential as effective treatment option for atopic dermatitis (AD); however, systemic exposure may cause potentially undesirable adverse reactions. In this study, we evaluated the relationship between the systemic exposure of E6005 and clinical parameters including skin condition and the incidence of AEs in patients with AD. Methods: The association analysis used the clinical data obtained in a previously conducted clinical study with topical E6005 in adult patients with AD. To estimate associations with drug exposure, generalized estimating equation logistic regression models were used, along with clinical data and plasma concentrations of M11, the major metabolite of E6005 (as an indicator for E6005 exposure). Results: The metabolite M11 was detected in 62 of 221 plasma samples from 72 subjects. From association analysis, SCORAD-A obtained prior to E6005 treatment was identified as the clinical parameter influenced to M11 detection with statistical significance (p = .003). M11 detection was not clearly associated with the incidence of adverse events occurred. Conclusion: Exposure to topical E6005 is associated with the eczema-associated area, however, that is not distinctly associated with its adverse drug reactions occurred after drug applications possibly due to E6005's characteristics of tissue distribution.


Assuntos
Dermatite Atópica/tratamento farmacológico , Ácidos Ftálicos/farmacocinética , Quinazolinas/farmacocinética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacocinética , Ácidos Ftálicos/metabolismo , Quinazolinas/metabolismo , Distribuição Tecidual , Resultado do Tratamento , Adulto Jovem
10.
Biomed Chromatogr ; 33(4): e4461, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30548501

RESUMO

Compound 27 {1, 12-bis[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]dodecane-1,12-dione} is a novel small molecule agonist of EphA2 receptor tyrosine kinase. It showed much improved activity for the activation of EphA2 receptor compared with the parental compound doxazosin. To support further pharmacological and toxicological studies of the compound, a method using liquid chromatography and electrospray ionization tandem mass spectrometry (LC-MS/MS) has been developed for the quantification of this compound. Liquid-liquid extraction was used to extract the compound from mouse plasma and brain tissue homogenate. Reverse-phase chromatography with gradient elution was performed to separate compound 27 from the endogenous molecules in the matrix, followed by MS detection using positive ion multiple reaction monitoring mode. Multiple reaction monitoring transitions m/z 387.3 → 290.1 and m/z 384.1 → 247.1 were selected for monitoring compound 27 and internal standard prazosin, respectively. The linear calibration range was 2-200 ng/mL with the intra- and inter-day precision and accuracy within the acceptable range. This method was successfully applied to the quantitative analysis of compound 27 in mouse plasma and brain tissue with different drug administration routes.


Assuntos
Cromatografia Líquida/métodos , Piperazinas/análise , Piperazinas/farmacocinética , Quinazolinas/análise , Quinazolinas/farmacocinética , Receptor EphA2/agonistas , Espectrometria de Massas em Tandem/métodos , Animais , Química Encefálica , Feminino , Modelos Lineares , Camundongos , Piperazinas/química , Quinazolinas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
11.
Clin Pharmacol Ther ; 105(2): 515-523, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29901213

RESUMO

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. In vitro, letermovir is a time-dependent inhibitor and an inducer of cytochrome P450 (CYP)3A, and an inhibitor of CYP2C8 and organic anion transporting polypeptide (OATP)1B. A stepwise approach was taken to qualify the interaction model of an existing letermovir physiologically based pharmacokinetic model to predict letermovir interactions with CYP3A and OATP1B. The model was then used to prospectively predict the interaction between letermovir and CYP2C8 substrates such as repaglinide, a substrate of CYP2C8, CYP3A, and OATP1B. The results showed that letermovir modestly increased the exposure of CYP2C8 substrates. These results were used to inform the US prescribing information in the absence of clinical drug-drug interaction studies. In addition, midazolam interactions with letermovir at therapeutic doses were also simulated to confirm that letermovir is a moderate CYP3A inhibitor.


Assuntos
Acetatos/farmacocinética , Antivirais/farmacocinética , Rotulagem de Medicamentos , Quinazolinas/farmacocinética , Adulto , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Infecções por Citomegalovirus/prevenção & controle , Interações de Medicamentos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Hipnóticos e Sedativos/efeitos adversos , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Masculino , Midazolam/efeitos adversos , Modelos Biológicos , Adulto Jovem
12.
Expert Opin Drug Metab Toxicol ; 14(12): 1197-1207, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30479172

RESUMO

INTRODUCTION: Letermovir is a new antiviral approved to prevent cytomegalovirus infection in hematopoietic stem cell transplant recipients. It has a distinct mechanism of action as it acts as a terminase complex inhibitor, and shows some advantages compared to the current treatment options for cytomegalovirus infection. Areas covered: This review focuses on the efficacy, safety, pharmacokinetics, pharmacodynamics, and drug-drug interactions of letermovir. Expert opinion: Letermovir is a new antiviral to prevent cytomegalovirus infection. Unlike the currently used polymerase inhibitors, it has a distinct mechanism of action with better safety, limited resistance, and no cross-resistance. Although a lot of research on pharmacokinetics and drug-drug interactions has already been performed, it might be useful to clarify the effect of letermovir on voriconazole exposure, the drug-drug interaction between caspofungine and letermovir and the effect of statins on letermovir exposure. Also, the lack of an exposure-response relationship should be confirmed in large real-life post-marketing studies in order to be able to lower the intravenous dose of letermovir.


Assuntos
Acetatos/administração & dosagem , Antivirais/administração & dosagem , Infecções por Citomegalovirus/prevenção & controle , Quinazolinas/administração & dosagem , Acetatos/farmacocinética , Acetatos/farmacologia , Antivirais/farmacocinética , Antivirais/farmacologia , Citomegalovirus , Infecções por Citomegalovirus/etiologia , Interações de Medicamentos , Farmacorresistência Viral , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Quinazolinas/farmacocinética , Quinazolinas/farmacologia
13.
Bioorg Med Chem Lett ; 28(21): 3483-3488, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30268702

RESUMO

A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization.


Assuntos
Proteínas Nucleares/antagonistas & inibidores , Quinazolinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Sítios de Ligação , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Proteínas Nucleares/química , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacocinética , Relação Estrutura-Atividade , Fatores de Transcrição/química
14.
Bioorg Med Chem Lett ; 28(20): 3333-3337, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217414

RESUMO

Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure-activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.


Assuntos
Aminopiridinas/farmacologia , Anemia/tratamento farmacológico , Hepcidinas/antagonistas & inibidores , Quinazolinas/farmacologia , Administração Oral , Aminopiridinas/administração & dosagem , Aminopiridinas/síntese química , Aminopiridinas/farmacocinética , Anemia/etiologia , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Desenho de Drogas , Hepcidinas/sangue , Hepcidinas/química , Humanos , Inflamação/induzido quimicamente , Inflamação/complicações , Interleucina-6/metabolismo , Ferro/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Quinazolinas/administração & dosagem , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Relação Estrutura-Atividade
15.
Mol Imaging ; 17: 1536012118795952, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30251592

RESUMO

CEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAFV600E), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496 ([11C]CEP-32496) as a positron emission tomography (PET) radiotracer to evaluate its pharmacokinetic properties and explore its potential for in vivo imaging. Following radiotracer synthesis, we performed in vitro binding assays and autoradiography of [11C]CEP-32496 in the A375 melanoma cell line and on tumor tissue sections from mice harboring the BRAFV600E mutation. These were followed by PET scans and biodistribution studies on nude mice bearing subcutaneous A375 cell-induced melanoma. [11C]CEP-32496 showed high binding affinity for BRAFV600E-positive A375 melanoma cells and densely accumulated in the respective tissue sections; this could be blocked by the BRAFV600E selective antagonist sorafenib and by unlabeled CEP-32496. The PET and biodistribution results revealed that [11C]CEP-32496 accumulated continuously but slowly into the tumor within a period of 0 to 60 minutes postinjection in A375-melanoma-bearing nude mice. Metabolite analysis showed high in vivo stability of [11C]CEP-32496 in plasma. Our results indicate that [11C]CEP-32496 has excellent specificity and affinity for the BRAFV600E mutation in vitro, while its noninvasive personalized diagnostic role needs to be studied further.


Assuntos
Melanoma/genética , Mutação/genética , Compostos de Fenilureia/farmacocinética , Proteínas Proto-Oncogênicas B-raf/genética , Quinazolinas/farmacocinética , Animais , Autorradiografia , Linhagem Celular Tumoral , Humanos , Lipídeos/química , Melanoma/sangue , Melanoma/urina , Camundongos Nus , Compostos de Fenilureia/sangue , Compostos de Fenilureia/química , Compostos de Fenilureia/urina , Quinazolinas/sangue , Quinazolinas/química , Quinazolinas/urina , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1097-1098: 74-82, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30205234

RESUMO

Most bioanalytical methods reported in literature for the quantitation of lapatinib in human plasma are either for lapatinib alone or lapatinib administered along with other tyrosine kinase inhibitors (TKIs) for therapeutic drug monitoring (TDM) in cancer patients. Recently there was a need for the quantitation of lapatinib in patients with end-stage renal disease (ESRD) receiving hemodialysis (HD). This special patient population normally receives many concomitant medications which have the potential to interfere with the quantitation of lapatinib. Here we describe an LC-MS-MS bioanalytical assay for the quantitation of lapatinib in human plasma containing potential concomitant medications which are commonly given to patients with ESRD receiving HD. The lapatinib calibration curve range was 2.50-1000 ng/mL. Lapatinib was fortified with its isotopically labeled internal standard in a 50 µL plasma aliquot and extracted with protein precipitation. The chromatographic separation was achieved on a Zorbax SB-C18 (5 µm, 2.1 × 50 mm) column with isocratic elution. Assay precision, accuracy, linearity, selectivity, sensitivity and analyte stability covering sample storage and analysis were established. No interferences were observed for the quantitation of lapatinib in the presence of concomitant medications. The validated LC-MS-MS method has been successfully applied to a clinical study for the determination of lapatinib concentrations in human plasma for patients with ESRD receiving HD.


Assuntos
Cromatografia Líquida/métodos , Falência Renal Crônica/terapia , Quinazolinas/sangue , Espectrometria de Massas em Tandem/métodos , Estabilidade de Medicamentos , Humanos , Falência Renal Crônica/complicações , Lapatinib , Modelos Lineares , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/uso terapêutico , Diálise Renal , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
AAPS PharmSciTech ; 19(7): 3277-3286, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30215168

RESUMO

Alfuzosin hydrochloride is an appropriate candidate drug to prepare a gastro-retention controlled release dosage form since it demonstrates a narrow absorption window in the proximal section of the gastrointestinal tract with a short half-life. The purpose of the present study was to develop and optimize a gastro-floating tablet of alfuzosin hydrochloride by using the compression coating method for controlling drug release in a controlled manner. The floating tablets were developed utilizing hydroxypropyl methylcellulose and carbomer as matrix materials. The impact of formulation factors on buoyancy property and in vitro drug release of the floating tablet was investigated. The "similarity factor" (f2) was used as the indicator for the optimization of the formulations. Furthermore, in vivo pharmacokinetic study in rabbits and correlation of in vitro/in vivo study were also performed. It was found that the optimized formulation F9 could float immediately less than 2 min and remain lastingly buoyant over 24 h and follow zero-order release kinetics well. In comparison with the commercially available prolonged release tablets XATRAL® XL, the prepared floating tablet exhibited similar pharmacokinetic parameters (Cmax, Tmax, t1/2, and AUC0 - t) and plasma concentration versus time profile. Moreover, it indicated from the correlation of in vitro/in vivo study that the floating tablets exhibited a good correlation of in vitro/in vivo. In summary, the compression coating gastro-floating tablets might be a promising drug delivery system for alfuzosin hydrochloride to control drug release.


Assuntos
Sistemas de Liberação de Medicamentos , Quinazolinas/administração & dosagem , Resinas Acrílicas/química , Animais , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Derivados da Hipromelose/química , Quinazolinas/química , Quinazolinas/farmacocinética , Coelhos , Comprimidos com Revestimento Entérico
18.
Eur J Pharm Sci ; 123: 459-474, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30077712

RESUMO

Vasicine (VAS) is a potential natural cholinesterase inhibitor for treatment of Alzheimer's disease. Due to one chiral centre (C-3) presenting in molecule, VAS has two enantiomers, d-vasicine (d-VAS) and l-vasicine (l-VAS). The study was undertaken to investigate the stereoselective glucuronidation metabolism, pharmacokinetics, anti-amnesic effect and acute toxicity of VAS enantiomers. In results, the glucuronidation metabolic rate of l-VAS was faster than d-VAS in human liver microsomes and isoenzymes tests, and it was proved that the UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B15 were the major metabolic enzymes for glucuronidation of l-VAS, while only UGT1A9 for d-VAS, which take responsibility of the significantly less metabolic affinity of d-VAS than l-VAS in HLM and rhUGT1A9. The plasma exposure of d-VAS in rats was 1.3-fold and 1.6-fold higher than that of l-VAS after intravenous and oral administration of d-VAS and l-VAS, respectively. And the plasma exposure of the major glucuronidation metabolite d-VASG was one of tenth of l-VASG or more less, no matter by intravenous or oral administration. Both d-VAS and l-VAS were exhibited promising acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, and the BChE inhibitory activity of d-VAS with IC50 of 0.03 ±â€¯0.001 µM was significantly stronger than that of l-VAS with IC50 of 0.98 ±â€¯0.19 µM. The molecular docking results indicated that d-VAS and l-VAS could bind to the catalytic active site (CAS position) either of human AChE and BChE, and the BChE combing ability of d-VAS (the score of GBI/WAS dG -7.398) was stronger than that of l-VAS (the score of GBI/WAS dG -7.135). Both d-VAS and l-VAS could improving the learning and memory on scopolamine-induced memory deficits in mice. The content of acetylcholine (ACh) after oral administration d-VAS increased more than that of l-VAS in mice cortex, through inhibiting cholinesterase (ChE) and increasing choline acetyltransferase (ChAT). In addition, the LD50 value of d-VAS (282.51 mg·kg-1) was slight lower than l-VAS (319.75 mg·kg-1). These results indicated that VAS enantiomers displayed significantly stereoselective metabolic, pharmacokinetics, anti-amnesic effect and toxic properties in vitro and in vivo. The d-VAS might be the dominant configuration for treating Alzheimer's disease.


Assuntos
Alcaloides/farmacocinética , Amnésia/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Inibidores da Colinesterase/farmacocinética , Glucuronídeos/metabolismo , Memória/efeitos dos fármacos , Quinazolinas/farmacocinética , Acetilcolinesterase/metabolismo , Administração Intravenosa , Administração Oral , Alcaloides/administração & dosagem , Alcaloides/química , Alcaloides/toxicidade , Amnésia/induzido quimicamente , Amnésia/psicologia , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Modelos Animais de Doenças , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Glucuronosiltransferase/metabolismo , Cobaias , Humanos , Isomerismo , Masculino , Taxa de Depuração Metabólica , Desintoxicação Metabólica Fase II , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/enzimologia , Simulação de Acoplamento Molecular , Quinazolinas/administração & dosagem , Quinazolinas/química , Quinazolinas/toxicidade , Coelhos , Ratos Sprague-Dawley , Escopolamina , Relação Estrutura-Atividade
19.
Drug Dev Ind Pharm ; 44(12): 1990-1999, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30058391

RESUMO

The purpose of this research was to develop multiple-unit gastric floating mini-tablets and to evaluate the possibility of using these mini-tablets as a delivery system to improve the drug absorption for drugs with a narrow absorption window. Mini-tablets were prepared using hydroxypropyl methylcellulose (HPMC K100M) and carbopol 971P as release retarding agents and sodium bicarbonate (NaHCO3) as gas-forming agent. The properties of the prepared mini-tablets in terms of floating characteristic parameters and in vitro release were evaluated. Furthermore, in vivo gastric retention study in rats and in vivo pharmacokinetic study in rabbits of the optimized formulation were performed. The optimized mini-tablets containing 45% HPMC K100M, 15% stearyl alcohol, 13% carbopol 971P, and 12% NaHCO3 were found to float immediately within 1 min and duration more than 9 h. The in vivo gastric retention study results indicated that the mini-tablets could retain in the stomach for more than 6.67 h. Furthermore, the AUC0-t of the floating mini-tablets (6849.83 ± 753.80 h ng·mL-1) was significantly higher than that of marketed sustained-release tablets XATRAL®XL (4970.16 ± 924.60 h ng·mL-1). All these results illustrated that the gastric floating mini-tablets might be a promising drug delivery system for drugs with a narrow absorption window.


Assuntos
Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Desenho de Drogas , Liberação Controlada de Fármacos , Quinazolinas/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Química Farmacêutica , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Excipientes/química , Mucosa Gástrica/metabolismo , Absorção Gastrointestinal , Masculino , Quinazolinas/administração & dosagem , Quinazolinas/química , Coelhos , Ratos , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Luz Próxima ao Infravermelho , Comprimidos , Fatores de Tempo
20.
Drugs Today (Barc) ; 54(6): 361-368, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29998227

RESUMO

Letermovir is a new antiviral agent with activity against human cytomegalovirus (CMV). Letermovir works as an inhibitor of the CMV DNA terminase complex which further inhibits viral DNA processing and packaging. Letermovir is available both orally and intravenously in 480-mg and 240-mg dosage forms, and is approved for use in the prophylaxis of CMV infection and disease in CMV-seropositive recipients of allogeneic hematopoietic stem cell transplant (HSCT) over the age of 18. The recommended dose is 480 mg p.o./i.v. once daily initiated between day 0 through day 28 post-allogeneic HSCT and continued through day 100 post-transplantation; the dose should be reduced to 240 mg daily if coadministered with cyclosporine. Letermovir is metabolized primarily by hepatic OATP1B1/3 and is not recommended for patients with severe hepatic impairment (Child-Pugh class C). Renal dosage adjustments are not warranted until a creatinine clearance (CrCl) of less than 10 mL/min; however, serum creatinine should be monitored when administered to patients with a CrCl of less than 50 mL/min. Cross-resistance with other useful antiviral agents in the treatment of CMV has not been observed. Additionally, letermovir is active against DNA polymerase inhibitor-resistant viral strains. Letermovir has shown promising clinical efficacy and is generally well tolerated, thus providing a favorable new option in the prophylaxis of CMV infection and disease.


Assuntos
Acetatos/uso terapêutico , Antivirais/uso terapêutico , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Quinazolinas/uso terapêutico , Acetatos/efeitos adversos , Acetatos/farmacocinética , Acetatos/farmacologia , Creatinina/sangue , Interações de Medicamentos , Humanos , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Quinazolinas/farmacologia
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