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1.
Drug Dev Ind Pharm ; 46(2): 318-328, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31976771

RESUMO

Uncontrolled distribution of nanoparticles (NPs) within the body can significantly decrease the efficiency of drug therapy and is considered among the main restrictions of NPs application. The aim of this study was to develop a depot combination delivery system (CDS) containing fingolimod loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) NPs dispersed into a matrix of oleic acid-grafted-aminated alginate (OA-g-AAlg) to minimize the nonspecific biodistribution (BD) of PHBV NPs. OA-g-AAlg was synthesized in two step; First, Alg was aminated by using adipic dihydrazide (ADH). The degree of hyrazide group substitution of Alg was determined by trinitro-benzene-sulfonic acid (TNBS) assay. Second, OA was attached to AAlg through formation of an amide bond. Chemical structure of OA-g-AAlg was confirmed with FTIR and HNMR spectroscopy. Furthermore, rheological properties of OA-g-AAlg with different grafting ratios were evaluated. In-vitro release studies indicated that 47% of fingolimod was released from the CDS within 28 days. Blood and tissue samples were analyzed using liquid chromatography/tandem mass spectrometry following subcutaneous (SC) injection of fingolimod-CDS into Wistar rats. The elimination phase half-life of CDS-fingolimod was significantly higher than that of fingolimod (∼32 d vs. ∼20 h). To investigate the therapeutic efficacy, lymphocyte count was assessed over a 40 day period in Wistar rats. Peripheral blood lymphocyte count decreased from baseline by 27 ± 8% in 2 days after injection. Overall, the designed CDS represented promising results in improving the pharmacokinetic properties of fingolimod. Therefore, we believe that this sustained release formulation has a great potential to be applied to delivery of various therapeutics.


Assuntos
Alginatos/química , Cloridrato de Fingolimode/química , Nanopartículas/química , Poliésteres/química , Animais , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Cloridrato de Fingolimode/farmacocinética , Cloridrato de Fingolimode/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual
2.
Acta Biomater ; 91: 209-219, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31029828

RESUMO

Oral cavity wound healing occurs in an environment that sustains ongoing physical trauma and is rich in bacteria. Despite this, injuries to the mucosal surface often heal faster than cutaneous wounds and leave less noticeable scars. Patients undergoing cleft palate repair have a high degree of wound healing complications with up to 60% experiencing oronasal fistula (ONF) formation. In this study, we developed a mouse model of hard palate mucosal injury, to study the endogenous injury response during oral cavity wound healing and ONF formation. Immunophenotyping of the inflammatory infiltrate following hard palate injury showed delayed recruitment of non-classical LY6Clo monocytes and failure to resolve inflammation. To induce a pro-regenerative inflammatory response, delivery of FTY720 nanofiber scaffolds following hard palate mucosal injury promoted complete ONF healing and was associated with increased LY6Clo monocytes and pro-regenerative M2 macrophages. Alteration in gene expression with FTY720 delivery included increased Sox2 expression, reduction in pro-inflammatory IL-1, IL-4 and IL-6 and increased pro-regenerative IL-10 expression. Increased keratinocyte proliferation during ONF healing was observed at day 5 following FTY720 delivery. Our results show that local delivery of FTY720 from nanofiber scaffolds in the oral cavity enhances healing of ONF, occurring through multiple immunomodulatory mechanisms. STATEMENT OF SIGNIFICANCE: Wound healing complications occur in up to 60% of patients undergoing cleft palate repair where an oronasal fistula (ONF) develops, allowing food and air to escape from the nose. Using a mouse model of palate mucosal injury, we explored the role of immune cell infiltration during ONF formation. Delivery of FTY720, an immunomodulatory drug, using a nanofiber scaffold into the ONF was able to attract anti-inflammatory immune cells following injury that enhanced the reepithelization process. ONF healing at day 5 following FTY720 delivery was associated with altered inflammatory and epithelial transcriptional gene expression, increased anti-inflammatory immune cell infiltration, and increased proliferation. These findings demonstrate the potential efficacy of immunoregenerative therapies to improve oral cavity wound healing.


Assuntos
Cloridrato de Fingolimode , Imunomodulação/efeitos dos fármacos , Palato Duro , Cicatrização , Animais , Citocinas/imunologia , Cloridrato de Fingolimode/química , Cloridrato de Fingolimode/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Nanofibras/química , Nanofibras/uso terapêutico , Palato Duro/imunologia , Palato Duro/lesões , Palato Duro/patologia , Fatores de Transcrição SOXB1/imunologia , Cicatrização/efeitos dos fármacos , Cicatrização/imunologia
3.
Free Radic Biol Med ; 137: 116-130, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31035004

RESUMO

Fingolimod is one of the few oral drugs available for the treatment of multiple sclerosis (MS), a chronic, inflammatory, demyelinating and neurodegenerative disease. The mechanism of action proposed for this drug is based in the phosphorylation of the molecule to produce its active metabolite fingolimod phosphate (FP) which, in turns, through its interaction with S1P receptors, triggers the functional sequestration of T lymphocytes in lymphoid nodes. On the other hand, part if not most of the damage produced in MS and other neurological disorders seem to be mediated by reactive oxygen species (ROS), and mitochondria is one of the main sources of ROS. In the present work, we have evaluated the anti-oxidant profile of FP in a model of mitochondrial oxidative damage induced by menadione (Vitk3) on neuronal cultures. We provide evidence that incubation of neuronal cells with FP alleviates the Vitk3-induced toxicity, due to a decrease in mitochondrial ROS production. It also decreases regulated cell death triggered by imbalance in oxidative stress (restore values of advanced oxidation protein products and total thiol levels). Also restores mitochondrial function (cytochrome c oxidase activity, mitochondrial membrane potential and oxygen consumption rate) and morphology. Furthermore, increases the expression and activity of protective factors (increases Nrf2, HO1 and Trx2 expression and GST and NQO1 activity), being some of these effects modulated by its interaction with the S1P receptor. FP seems to increase mitochondrial stability and restore mitochondrial dynamics under conditions of oxidative stress, making this drug a potential candidate for the treatment of neurodegenerative diseases other than MS.


Assuntos
Antioxidantes/farmacologia , Neurônios Dopaminérgicos/metabolismo , Cloridrato de Fingolimode/farmacologia , Mitocôndrias/metabolismo , Esclerose Múltipla/tratamento farmacológico , Receptores de Esfingosina-1-Fosfato/metabolismo , Animais , Morte Celular , Linhagem Celular , Neurônios Dopaminérgicos/patologia , Cloridrato de Fingolimode/química , Cloridrato de Fingolimode/uso terapêutico , Humanos , Lisofosfolipídeos/metabolismo , Potencial da Membrana Mitocondrial , Camundongos , Mimetismo Molecular , Neuroproteção , Estresse Oxidativo/efeitos dos fármacos , Consumo de Oxigênio , Fosfatos/química , Espécies Reativas de Oxigênio/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Vitamina K 3/toxicidade
4.
Bioorg Med Chem Lett ; 28(23-24): 3585-3591, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30409535

RESUMO

Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P1) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein-coupled receptor (GPCR) in an attempt to suppress autoimmune disorders. FTY720, also known as fingolimod, is the first oral disease-modifying therapy for MS on the market. In pursuit of improved stability, bioavailability, and efficiency, structural analogues of this initial prodrug have emerged over time. This review covers a brief introduction to the sphingolipid metabolism, the mechanism of action on S1P1, and an updated overview of synthetic sphingosine S1P1 agonists.


Assuntos
Doenças Autoimunes/patologia , Receptores de Lisoesfingolipídeo/metabolismo , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Disponibilidade Biológica , Cloridrato de Fingolimode/química , Cloridrato de Fingolimode/farmacocinética , Cloridrato de Fingolimode/uso terapêutico , Humanos , Imunossupressores/química , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Oxidiazóis/química , Oxidiazóis/farmacocinética , Oxidiazóis/uso terapêutico , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Esfingolipídeos/metabolismo
5.
Chem Pharm Bull (Tokyo) ; 66(10): 1015-1018, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30270236

RESUMO

FTY720 is employed for the treatment of multiple sclerosis and exerts apoptotic effects on various cancers through protein phosphatase 2A (PP2A) activation. In compound 4, the dihydroxy head group of FTY720 was modified into dihydroxy phenyl group. The cell survival in compound 4 treated colorectal and gastric cancer cells was significantly reduced as compared with control, 34.6 and 25.1%, respectively. The docking study of compound 4 showed that the aromatic head group effectively binds to PP2A.


Assuntos
Antineoplásicos/farmacologia , Cloridrato de Fingolimode/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Cloridrato de Fingolimode/síntese química , Cloridrato de Fingolimode/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
Eur J Med Chem ; 159: 217-242, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30292898

RESUMO

A series of compounds containing pyrrolidine and pyrrolizidine cores with appended hydrophobic substituents were prepared as constrained analogs of FTY720 and phytosphingosine. The effect of these compounds on the viability of cancer cells, on downregulation of the nutrient transport systems, and on their ability to cause vacuolation was studied. An attempt to inhibit HDACs with some phosphate esters of our analogs was thwarted by our failure to reproduce the reported inhibitory action of FTY720-phosphate.


Assuntos
Antineoplásicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Cloridrato de Fingolimode/farmacologia , Esfingosina/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Cloridrato de Fingolimode/análogos & derivados , Cloridrato de Fingolimode/química , Camundongos , Estrutura Molecular , Esfingosina/síntese química , Esfingosina/química , Esfingosina/farmacologia , Relação Estrutura-Atividade
7.
Chem Commun (Camb) ; 54(85): 12002-12005, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30221278

RESUMO

The direct, catalytic vicinal difluorination of terminal alkenes via an I(i)/I(iii) manifold was exploited to install a chiral, hybrid bioisostere of the CF3 and Et groups (BITE) in Gilenya®; the first orally available drug for the clinical management of Multiple Sclerosis (MS). This subtle fluorination pattern allows lipophilicity (log D) to be tempered compared to the corresponding CF3 and Et derivatives (CH2CH3 > CH2CF3 > CHFCH2F).


Assuntos
Cloridrato de Fingolimode/análogos & derivados , Cloridrato de Fingolimode/química , Imunossupressores/química , Animais , Estabilidade de Medicamentos , Cloridrato de Fingolimode/síntese química , Halogenação , Hepatócitos/efeitos dos fármacos , Humanos , Imunossupressores/síntese química , Microssomos Hepáticos/metabolismo , Esclerose Múltipla/tratamento farmacológico , Ratos
8.
J Cell Mol Med ; 22(6): 3159-3166, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29536648

RESUMO

Fingolimod (FTY720) is used as an immunosuppressant for multiple sclerosis. Numerous studies indicated its neuroprotective effects in stroke. However, the mechanism remains to be elucidated. This study was intended to investigate the mechanisms of phosphorylated FTY720 (pFTY720), which was the principle active molecule in regulating astrocyte-mediated inflammatory responses induced by oxygen-glucose deprivation (OGD). Results demonstrated that pFTY720 could protect astrocytes against OGD-induced injury and inflammatory responses. It significantly decreased pro-inflammatory cytokines, including high mobility group box 1 (HMGB1) and tumour necrosis factor-α (TNF-α). Further, studies displayed that pFTY720 could prevent up-regulation of Toll-like receptor 2 (TLR2), phosphorylation of phosphoinositide 3-kinase (PI3K) and nuclear translocation of nuclear factor kappa B (NFκB) p65 subunit caused by OGD. Sphingosine-1-phosphate receptor 3 (S1PR3) knockdown could reverse the above change. Moreover, administration of TLR2/4 blocker abolished the protective effects of pFTY720. Taken together, this study reveals that pFTY720 depends on S1PR3 to protect astrocytes against OGD-induced neuroinflammation, due to inhibiting TLR2/4-PI3K-NFκB signalling pathway.


Assuntos
Cloridrato de Fingolimode/farmacologia , Inflamação/tratamento farmacológico , Receptores de Lisoesfingolipídeo/genética , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Animais , Astrócitos/efeitos dos fármacos , Carência Cultural , Citocinas/genética , Modelos Animais de Doenças , Cloridrato de Fingolimode/química , Proteína HMGB1/genética , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Inflamação/genética , Inflamação/patologia , NF-kappa B/genética , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Cultura Primária de Células , Ratos , Receptores de Lisoesfingolipídeo/química , Transdução de Sinais/efeitos dos fármacos , Receptores de Esfingosina-1-Fosfato , Fator de Necrose Tumoral alfa/genética
9.
J Biomed Mater Res B Appl Biomater ; 106(2): 555-568, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28240814

RESUMO

Macroencapsulation is a powerful approach to increase the efficiency of extrahepatic pancreatic islet transplant. FTY720, a small molecule that activates signaling through sphingosine-1-phosphate receptors, is immunomodulatory and pro-angiogenic upon sustained delivery from biomaterials. While FTY720 (fingolimod, Gilenya) has been explored for organ transplantation, in the present work the effect of locally released FTY720 from novel nanofiber-based macroencapsulation membranes is explored for islet transplantation. We screened islet viability during culture with FTY720 and various biodegradable polymers. Islet viability is significantly reduced by the addition of high doses (≥500 ng/mL) of soluble FTY720. Among the polymers screened, islets have the highest viability when cultured with poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). Therefore, PHBV was blended with polycaprolactone (PCL) for mechanical stability and electrospun into nanofibers. Islets had no detectable function ex vivo following 5 days or 12 h of subcutaneous implantation within our engineered device. Subsequently, we explored a preconditioning scheme in which islets are transplanted 2 weeks after FTY720-loaded nanofibers are implanted. This allows FTY720 to orchestrate a local regenerative milieu while preventing premature transplantation into avascular sites that contain high concentrations of FTY720. These results provide a foundation and motivation for further investigation into the use of FTY720 in preconditioning sites for efficacious islet transplantation. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 555-568, 2018.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Cloridrato de Fingolimode/administração & dosagem , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas/efeitos dos fármacos , Membranas Artificiais , Animais , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode/química , Humanos , Ilhotas Pancreáticas/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nanofibras/química , Poliésteres/química , Poliésteres/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Estreptozocina/farmacologia
10.
Nat Commun ; 8(1): 1163, 2017 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-29079828

RESUMO

G protein-coupled receptors (GPCRs), a superfamily of cell-surface receptors involved in virtually all physiological processes, are the major target class for approved drugs. Imaging GPCR activation in real time in living animals would provide a powerful way to study their role in biology and disease. Here, we describe a mouse model that enables the bioluminescent detection of GPCR activation in real time by utilizing the clinically important GPCR, sphingosine-1-phosphate receptor 1 (S1P1). A synthetic S1P1 signaling pathway, designed to report the interaction between S1P1 and ß-arrestin2 via the firefly split luciferase fragment complementation system, is genetically encoded in these mice. Upon receptor activation and subsequent ß-arrestin2 recruitment, an active luciferase enzyme complex is produced, which can be detected by in vivo bioluminescence imaging. This imaging strategy reveals the dynamics and spatial specificity of S1P1 activation in normal and pathophysiologic contexts in vivo and can be applied to other GPCRs.


Assuntos
Luminescência , Receptores de Lisoesfingolipídeo/metabolismo , beta-Arrestina 2/metabolismo , Alelos , Animais , Membrana Celular/metabolismo , Células-Tronco Embrionárias/citologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Cloridrato de Fingolimode/química , Teste de Complementação Genética , Proteínas de Fluorescência Verde/metabolismo , Heterozigoto , Homozigoto , Inflamação , Ligantes , Luciferases/metabolismo , Camundongos , Transdução de Sinais , Esfingolipídeos/química
11.
Drugs ; 77(16): 1755-1768, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28905255

RESUMO

Since the approval of fingolimod, several selective sphingosine-1-phosphate receptor modulators have entered clinical development for multiple sclerosis. However, side effects can occur with sphingosine-1-phosphate receptor modulators. By considering short-term data across the drug class and longer term fingolimod data, we aim to highlight the potential of sphingosine-1-phosphate receptor modulators in multiple sclerosis, while offering reassurance that their benefit-risk profiles are suitable for long-term therapy. Short-term fingolimod studies demonstrated the efficacy of this drug class, showed that cardiac events upon first-dose administration are transient and manageable, and showed that serious adverse events are rare. Early-phase studies of selective sphingosine-1-phosphate receptor modulators also show efficacy with a similar or improved safety profile, and treatment initiation effects were reduced with dose titration. Longer term fingolimod studies demonstrated sustained efficacy and raised no new safety concerns, with no increases in macular edema, infection, or malignancy rates. Switch studies identified no safety concerns and greater patient satisfaction and persistence with fingolimod when switching from injectable therapies with no washout period. Better outcomes were seen with short than with long washouts when switching from natalizumab. The specific immunomodulatory effects of sphingosine-1-phosphate receptor modulators are consistent with the low observed rates of long-term, drug-related adverse effects with fingolimod. Short-term data for selective sphingosine-1-phosphate receptor modulators support their potential effectiveness in multiple sclerosis, and improved side-effect profiles may widen patient access to this drug class. The long-term safety, tolerability, and persistence profiles of fingolimod should reassure clinicians that sphingosine-1-phosphate receptor modulators are likely to be suitable for the long-term treatment of multiple sclerosis.


Assuntos
Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/farmacologia , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Receptores de Lisoesfingolipídeo/metabolismo , Cloridrato de Fingolimode/efeitos adversos , Cloridrato de Fingolimode/química , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/química , Imunossupressores/farmacologia , Esclerose Múltipla/imunologia , Natalizumab/administração & dosagem , Natalizumab/efeitos adversos , Natalizumab/química , Natalizumab/farmacologia , Medição de Risco
12.
Sci Rep ; 7(1): 5958, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28729700

RESUMO

Neurotransmission and secretion of hormones involve a sequence of protein/lipid interactions with lipid turnover impacting on vesicle trafficking and ultimately fusion of secretory vesicles with the plasma membrane. We previously demonstrated that sphingosine, a sphingolipid metabolite, promotes formation of the SNARE complex required for membrane fusion and also increases the rate of exocytosis in isolated nerve terminals, neuromuscular junctions, neuroendocrine cells and in hippocampal neurons. Recently a fungi-derived sphingosine homologue, FTY720, has been approved for treatment of multiple sclerosis. In its non-phosphorylated form FTY720 accumulates in the central nervous system, reaching high levels which could affect neuronal function. Considering close structural similarity of sphingosine and FTY720 we investigated whether FTY720 has an effect on regulated exocytosis. Our data demonstrate that FTY720 can activate vesicular synaptobrevin for SNARE complex formation and enhance exocytosis in neuroendocrine cells and neurons.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Sistemas Neurossecretores/metabolismo , Proteínas R-SNARE/metabolismo , Esfingosina/análogos & derivados , Vesículas Sinápticas/metabolismo , Animais , Citosol/efeitos dos fármacos , Citosol/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Exocitose/efeitos dos fármacos , Cloridrato de Fingolimode/química , Cloridrato de Fingolimode/farmacologia , Ácido Glutâmico/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Esclerose Múltipla/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/patologia , Sistemas Neurossecretores/fisiopatologia , Ratos Wistar , Proteínas SNARE/metabolismo , Vesículas Sinápticas/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
13.
J Med Chem ; 60(13): 5267-5289, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28291340

RESUMO

The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the various proteins involved in the interconversion of the ligands, or targeting the receptors that respond to the ligands. The focus of this article is on the most advanced of the sphingosine-related therapeutics, agonists of sphingosine-1-phosphate receptor 1 (S1P1). The diverse structural classes of S1P1 agonists will be discussed and the status of compounds of clinical relevance will be detailed. An examination of how potential safety concerns are being navigated with compounds currently under clinical evaluation is followed by a discussion of the novel methods being explored to identify next-generation S1P1 agonists with improved safety profiles. Finally, therapeutic opportunities for sphingosine-related targets outside of S1P1 are touched upon.


Assuntos
Cloridrato de Fingolimode/farmacologia , Lisofosfolipídeos/metabolismo , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/análogos & derivados , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode/química , Humanos , Ligantes , Estrutura Molecular , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/metabolismo , Relação Estrutura-Atividade
14.
Yale J Biol Med ; 90(1): 15-23, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28356890

RESUMO

Multiple Sclerosis (MS) is a chronic autoimmune disorder affecting the Central Nervous System (CNS) through inflammation, demyelination and neurodegeneration. Sphingosine-1-phosphate receptor (S1PR1) modulators have been approved for the management of MS. Phosphorylated fingolimod mimics endogenous sphingosine-1-phosphate (S1P), a bioactive lipid that regulates remyelination and cell injury. Amiselimod was developed as a successor of fingolimod, with more specificity for S1PR1, and showed promising results until phase 2 clinical trials. This study utilized the fingolimod and amiselimod scaffolds, together with their critical binding interactions for the S1PR1 Ligand Binding Pocket, as templates for the in silico de novo design of high efficiency binding Lipinski rule-compliant molecules. A rigorous selection process identified two molecules, Molecules 003 and 019, deriving from fingolimod and amiselimod, respectively, which were deemed most suitable for further optimization.


Assuntos
Fatores Imunológicos/uso terapêutico , Lisofosfolipídeos/metabolismo , Esclerose Múltipla/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/análogos & derivados , Algoritmos , Animais , Cristalografia por Raios X , Desenho de Fármacos , Cloridrato de Fingolimode/química , Humanos , Fatores Imunológicos/química , Estrutura Molecular , Esclerose Múltipla/tratamento farmacológico , Estrutura Secundária de Proteína , Esfingosina/metabolismo
15.
J Pharm Sci ; 106(1): 176-182, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27666377

RESUMO

Formulation of a nanoparticulate Fingolimod delivery system based on biodegradable poly(3-hydroxybutyrate-co-3-hydroxyvalerate) was optimized according to artificial neural networks (ANNs). Concentration of poly(3-hydroxybutyrate-co-3-hydroxyvalerate), PVA and amount of Fingolimod is considered as the input value, and the particle size, polydispersity index, loading capacity, and entrapment efficacy as output data in experimental design study. In vitro release study was carried out for best formulation according to statistical analysis. ANNs are employed to generate the best model to determine the relationships between various values. In order to specify the model with the best accuracy and proficiency for the in vitro release, a multilayer percepteron with different training algorithm has been examined. Three training model formulations including Levenberg-Marquardt (LM), gradient descent, and Bayesian regularization were employed for training the ANN models. It is demonstrated that the predictive ability of each training algorithm is in the order of LM > gradient descent > Bayesian regularization. Also, optimum formulation was achieved by LM training function with 15 hidden layers and 20 neurons. The transfer function of the hidden layer for this formulation and the output layer were tansig and purlin, respectively. Also, the optimization process was developed by minimizing the error among the predicted and observed values of training algorithm (about 0.0341).


Assuntos
Portadores de Fármacos/química , Cloridrato de Fingolimode/administração & dosagem , Imunossupressores/administração & dosagem , Nanopartículas/química , Poliésteres/química , Algoritmos , Teorema de Bayes , Liberação Controlada de Fármacos , Cloridrato de Fingolimode/química , Imunossupressores/química , Modelos Químicos , Redes Neurais de Computação , Tamanho da Partícula
16.
J Med Chem ; 59(21): 9837-9854, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27726358

RESUMO

Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound 10 had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model.


Assuntos
Desenho de Fármacos , Cloridrato de Fingolimode/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Cães , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/química , Adjuvante de Freund/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Ligantes , Linfócitos/efeitos dos fármacos , Macaca fascicularis , Masculino , Camundongos , Estrutura Molecular , Mycobacterium/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Distribuição Tecidual
17.
Curr Med Chem ; 23(38): 4286-4296, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27758717

RESUMO

BACKGROUND: The serine-threonine protein phosphatase 2A (PP2A) regulates multiple cell signaling cascades and its inactivation by viral oncoproteins, mutation of specific structural subunits or upregulation of the cellular endogenous inhibitors may contribute to malignant transformation by regulating specific phosphorylation events. Pharmacological modulation of PP2A activity is becoming an attractive strategy for cancer treatment. Some compounds targeting PP2A are able to induce PP2A reactivation and subsequent cell death in several types of cancer. METHODS: We undertook a search of bibliographic databases for peer-reviewed articles focusing on the main item of the review. We selected articles published in indexed journals. The quality of retrieved papers was appraised using the standard bibliometric indicators. RESULTS: One hundred and fourteen papers were included in the review. Twenty-seven papers gave an overview of structure and physiological role of PP2A. Twenty-five papers outlined the role of PP2A in tumor suppression. Forty papers analyzed the mechanism involved in PP2A reactivation by synthetic compounds, and twenty-two papers outlined the capability of natural compounds of restoring PP2A activity and how this could be beneficial. CONCLUSION: Findings analyzed in this review underline the central role of PP2A as a regulator of cell growth and survival, hence its function as tumor suppressor. The discovery that some compounds, either synthetic or natural, are capable of reactivating PP2A opens up new perspectives for future strategies to fully exploit therapeutic potential in human cancer. Thus, this review could also be of particular interest to pharmaceutical or biotechnology companies for drug design and targeted delivery.


Assuntos
Proteína Fosfatase 2/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , Bortezomib/química , Bortezomib/uso terapêutico , Cloridrato de Fingolimode/química , Cloridrato de Fingolimode/uso terapêutico , Humanos , Imunossupressores/química , Imunossupressores/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/química , Proteínas Proto-Oncogênicas c-akt/metabolismo
18.
Org Biomol Chem ; 14(20): 4605-16, 2016 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-27102578

RESUMO

AAL(S), the chiral deoxy analog of the FDA approved drug FTY720, has been shown to inhibit proliferation and apoptosis in several cancer cell lines. It has been suggested that it does this by activating protein phosphatase 2A (PP2A). Here we report the synthesis of new cytotoxic analogs of AAL(S) and the evaluation of their cytotoxicity in two myeloid cell lines, one of which is sensitive to PP2A activation. We show that these analogs activate PP2A in these cells supporting the suggested mechanism for their cytotoxic properties. Our findings identify key structural motifs required for anti-cancer effects.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Cloridrato de Fingolimode/síntese química , Cloridrato de Fingolimode/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Proteína Fosfatase 2/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Ativação Enzimática/efeitos dos fármacos , Cloridrato de Fingolimode/química , Cloridrato de Fingolimode/uso terapêutico , Leucemia Mieloide Aguda/enzimologia
19.
AAPS PharmSciTech ; 17(4): 907-14, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26729522

RESUMO

Fingolimod (FNGL) is an immune-modulatory agent prescribed for relapsing forms of multiple sclerosis. Because of its mechanism of action, FNGL is potentially a treatment for chronic, non-curable T-lymphocyte-driven inflammatory skin diseases (TLDISD) such as psoriasis and atopic dermatitis. Since severe side effects limit the systemic administration of FNGL, the objective of this study is to develop a hydroxypropyl cellulose (2%) FNGL gel for dermatological applications. First, the effect of FNGL strength (0.05%, 0.10%, 0.50%, and 1.00%) on skin permeability and retention was investigated. We carried out several permeation studies with vertical Franz diffusion cells and (i) cellulose or (ii) excised dorsal porcine ear skin (EDPES) as membrane. We also quantified FNGL in the stratum corneum and in dermis with the tape-stripping method. Permeability parameters as well as the amount retained in skin increased significantly (p < 0.01) with strength; however, there was no statistically significant difference between the 0.50% and 1.00% gels for both cellulose and EDPES. Therefore, we selected the 0.50% gel to investigate the effect of colloidal oatmeal (0%, 1%, 3%, 6%, and 10%) on FNGL in vitro permeability and skin retention. Colloidal oatmeal has beneficial dermatological properties for TLDISD and may complement FNGL activity. Permeability increased significantly (p < 0.001) with colloidal oatmeal at the 6% and 10% strength with an enhancement ratio of 3.5 and 2.4, respectively, whereas the amount retained in the skin decreased significantly (p < 0.001) compared to the base gel. In conclusion, the 0.50% FNGL(.)HCL gel with 6% Aveeno® has very promising permeability characteristics for delivery of FNGL to the skin.


Assuntos
Coloides/química , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/química , Géis/administração & dosagem , Géis/química , Pele/metabolismo , Administração Cutânea , Animais , Química Farmacêutica/métodos , Permeabilidade , Absorção Cutânea , Suínos
20.
Curr Med Chem ; 23(3): 242-64, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26639095

RESUMO

It is accepted that sphingolipids (SL) are not only structural lipids in cellular membranes, but also key regulators of different cell process. Sphingosine-1-phosphate (S1P) is a member of this family involved, inter alia, in cell migration, angiogenesis and cell proliferation processes, being able to play different intracellular and extracellular roles. When S1P is transported out of the cell, it binds S1P specific G protein-coupled receptors, which are mainly involved in the regulation of the immune, vascular and nervous systems. These effects account for the vast diversity of functions that arise from the activation of S1P receptors. Deregulation of S1P levels is correlated with several pathologies, such as autoimmune disorders and cancer. Consequently, the correct modulation of these receptors represents a valuable approach for the development of new therapeutic strategies. Along this line, the non-selective S1P receptor agonist fingolimod (FTY720) has been commercialized recently for the treatment of multiple sclerosis and several related S1P receptor modulators are ongoing clinical trials. However, despite the progress in this field, the biological functions of S1P receptors are not still well elucidated. For this reason, several studies are being developed in order to better understand the functions of these receptors, making use of new selective S1P receptor agonists and antagonists as pharmacological tools.


Assuntos
Receptores de Lisoesfingolipídeo/metabolismo , Cloridrato de Fingolimode/química , Cloridrato de Fingolimode/uso terapêutico , Humanos , Sistema Imunitário/metabolismo , Imunossupressores/química , Imunossupressores/uso terapêutico , Lisofosfolipídeos/química , Lisofosfolipídeos/metabolismo , Esclerose Múltipla/tratamento farmacológico , Sistema Nervoso/metabolismo , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Esfingolipídeos/química , Esfingolipídeos/uso terapêutico , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/metabolismo
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