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1.
Chin J Integr Med ; 26(2): 114-121, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31144159

RESUMO

OBJECTIVE: To investigate the effect of quercetin on ATP binding cassette transporter A1 (ABCA1), liver X receptor (LXR), and proprotein convertase subtilisin/kexin type 9 (PCSK9) expressions in apoE-knockout (ApoE-/-) mice. METHODS: The high-fat diet-induced atherosclerosis (AS) in ApoE-/- mice was established. Thirty-six mice were divided into 3 groups using random number table method: model group (n=12), quercetin group (n=12), and atorvastatin group (n=12), with C57BL/6J mice of the same strain and age as the control group (n=12). Quercetin group and atorvastatin group were administrated with quercetin and atorvastatin by oral gavage, with doses of 12.5 and 4 mg/(kg•d), respectively. Animals in the control and model groups were given an equal volume of distilled water by oral gavage once per day for a total of 12 weeks. Western blot and immunohistochemical methods were employed to determine the aortic ABCA1, LXR-α and PCSK9 protein expression. Enzyme linked immunosorbent assay method was used to detect the expression of serum total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-10, combined with tissue pathological examination. RESULTS: ApoE-/- mice fed with a high-fat diet had notable atherosclerosis lesions, with reduced ABCA1, LXR-α and IL-10 levels (all P<0.01), elevated PCSK9, TNF-α and IL-6 expression, and increased TC and LDL-C contents (all P<0.01). After quercetin intervention, the areas of AS plaques and the expressions of PCSK9, TNF-α and IL-6 were significantly reduced (all P<0.01), while the expressions of ABCA1 and LXR-α were increased significantly (all P<0.01). CONCLUSION: Quercetin effectively interfered with AS development by regulating the expressions of ABCA1, LXR- α and PCSK9 in ApoE-/- mice.

2.
Eur J Pharmacol ; 865: 172748, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31655030

RESUMO

To test the hypothesis that the flavonoid compound, fisetin, protects macrophages from lipid accumulation and senescence through regulation of casein kinase 2-interacting protein-1 (CKIP-1)/REGγ (11S regulatory particles, 28 kDa proteasome activator, proteasome activator subunit 3) signaling. RAW264.7 macrophage cells were exposed to 100 µg/ml oxidized low-density lipoprotein (ox-LDL) with or without 20 µg/ml fisetin for 24 h. Cell viability was detected by CCK-8 after 1 h. Intracellular lipid accumulation was measured using Oil Red O staining. Total cholesterol (TC) and free cholesterol (FC) contents were measured using assay kits, and cell senescence was inferred by ß-gal staining. Protein expression levels of CKIP-1, REGγ, organic cation transporter 1 (Oct-1), lectin-like oxidized LDL receptor-1 (LOX-1), tumor suppressor protein p53 (p53), cell cycle regulatory protein p21 (p21), and multiple tumor suppressor-1 (p16) were detected by immunofluorescence and confirmed by Western blot. Stimulating RAW264.7 macrophage cells with 100 µg/ml ox-LDL for 24 h induced the formation of foam cells, increased intracellular lipid accumulation, increased TC and FC content, and promoted cell senescence. Furthermore, cells induced with 100 µg/ml ox-LDL for 24 h showed decreased CKIP-1 and REGγ protein, while the expressions of Oct-1, LOX-1, p53, p21 and p16 were increased. In contrast, treatment with 20 µg/ml fisetin reversed 100 µg/ml ox-LDL effects to increase cell viability, and decrease ß-gal staining, intracellular lipid levels and TC and FC levels. These beneficial effects were associated with increased CKIP-1 and REGγ and decreased Oct-1, LOX-1, p53, p21, and p16 protein expression. Results indicated that fisetin limited ox-LDL-mediated lipid accumulation and senescence in RAW264.7 macrophage-derived foam cells. The mechanism underlying these effects may involve regulation of CKIP-1/REGγ signaling.

3.
J Integr Med ; 17(6): 404-409, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31548147

RESUMO

OBJECTIVE: To investigate the effect and underlying mechanisms of Tiaoxin Recipe (a Chinese herbal formula) treatment on Alzheimer's disease (AD). METHODS: Twelve-week-old APPswe/PS1ΔE9 (APP/PS1) double transgenic mice were used as a model of AD-afflicted mice. One group of mice was treated with Tiaoxin Recipe by gastrogavage for 12 weeks, while two other groups were given intraperitoneal injections of nicotinamide adenine dinucleotide or FK866 for 4 weeks. Morris water maze and thioflavin S staining tests were performed to evaluate cognitive impairment and amyloid plaque deposition, respectively. Serum amyloid-ß1-42 (Aß1-42) content was detected using an enzyme-linked immunosorbent assay, and quantitative reverse transcription-polymerase chain reaction was performed to examine the expression levels of microRNA-34a (miR-34a) in cortex and hippocampus samples of the study mice. RESULTS: Compared with the normal control group, the memory and learning abilities of the APP/PS1 model group were found to be impaired (P < 0.01), as shown by the increased levels of senile plaque deposition in cortex and hippocampus (P < 0.01), miR-34a expression (P < 0.01) and serum Aß1-42 content (P < 0.01). Treatment with Tiaoxin Recipe significantly reduced memory impairment (P < 0.01) by reducing amyloid plaque accumulation in cortex and hippocampus (P < 0.01), miR-34a expression (P < 0.01) and serum Aß1-42 content (P < 0.01) in APP/PS1 mice. CONCLUSION: Tiaoxin Recipe is a viable complementary or alternative therapeutic treatment that is capable of delaying the development of early-stage AD by inhibiting the expression of miR-34a.

4.
Mol Imaging Biol ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31321650

RESUMO

PURPOSE: Prostate-specific membrane antigen (PSMA) continues to be the hallmark biomarker for prostate cancer as it is expressed on nearly all prostatic tumors. In addition, increased PSMA expression correlates with castration resistance and progression to the metastatic stage of the disease. Recently, we combined both an albumin-binding motif and an irreversible PSMA inhibitor to develop the novel PSMA-targeted radiotherapeutic agent, CTT1403. This molecule was novel in the field of PSMA-targeted agents as its key motifs resulted in extended blood circulation time and tumor uptake, rapid and extensive internalization into PSMA+ cells, and promising therapeutic efficacy. The objective of this study was to perform IND-enabling translational studies on CTT1403 in rodent models. PROCEDURES: A dose optimization study was performed in PC3-PIP (PSMA+) tumor-bearing mice. Treatment groups were randomly selected to receive one to three 14-MBq injections of CTT1403. Control groups included (1) saline, (2) non-radioactive [175Lu]CTT1403, or (3) two injections of 14 MBq CTT1751, a Lu-177-labeled non-targeted albumin-binding moiety. Tumor growth was monitored up to 120 days. Small-animal single photon emission tomography/X-ray computed tomography imaging was performed with CTT1403 and CTT1751 in PC3-PIP tumor-bearing mice to visualize infiltration of the Lu-177-labeled agent into the tumor. In preparation for a first-in-human study, human absorbed doses were estimated based on rat biodistribution out to 5 weeks to determine a safe CTT1403 therapy dose in humans. RESULTS: Two to 3 injections of 14 MBq CTT1403 yielded significant tumor growth inhibition and increased survival compared with all control groups and mice receiving 1 injection of 14 MBq CTT1403. Five of 12 mice receiving 2 or 3 injections of CTT1403 survived to the 120-day post-treatment study endpoint. Dosimetry identified the kidneys as the dose-limiting organ, with an equivalent dose of 5.18 mSv/MBq, resulting in a planned maximum dose of 4.4 GBq for phase 1 clinical trials. CONCLUSIONS: The preclinical efficacy and dosimetry of CTT1403 suggest that this agent has significant potential to be safe and effective in humans.

5.
ACS Med Chem Lett ; 10(3): 367-373, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891142

RESUMO

A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRß. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.

6.
J Med Chem ; 62(5): 2265-2285, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.

7.
Bosn J Basic Med Sci ; 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30684953

RESUMO

Mutations in the guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) gene are rare. To date, 72 cases with GMPPB gene mutations have been reported. Herein, we reported a case of a 29-year-old Chinese male presenting with limb-girdle muscular dystrophy (LGMD) who was found to have two heterozygous GMPPB mutations. The patient had a progressive limb weakness for 19 years. His parents and elder brother were normal. On examination he had a waddling gait, and absent tendon reflexes in all four limbs. Electromyography showed myogenic damage. Muscle magnetic resonance imaging (MRI) showed fatty degeneration in the bilateral medial thigh muscles. High throughput gene panel sequencing revealed that the patient carried compound heterozygous mutations in the GMPPB gene, c.553C>T (p.R185C, maternal inheritance) and c.346C>T (p.P116S, paternal inheritance). This case provides additional information regarding the phenotypic spectrum of GMPPB mutations in the Chinese population.

8.
Talanta ; 195: 655-661, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30625597

RESUMO

3-Nitrotyrosine (3-NT) is thought to be a relevant biomarker of nitrosative stress which is associated with many inflammatory and chronic diseases. It is necessary to develop confidential method for specific and sensitive 3-NT detection. In this paper, on the basis of anti-3-NT specific antibody, we developed a label-free indirect competitive surface plasmon resonance (SPR) immunosensor and ELISA for the detection of 3-NT. Under the optimized conditions, the SPR immunosensor can obtain a linear range of 0.17-6.07 µg/mL and a limit of detection (LOD) of 0.12 µg/mL while the ELISA can reach 0.33-9.94 µg/mL and a LOD of 0.24 µg/mL.The selectivity of 3-NT was also testified by six kinds of amino acid analogues. Besides, the developed SPR immunosensor was compared thoroughly with a conventional ELISA in spiked analysis of urine samples. Good recoveries and correlation between these two methods were observed (R2 = 0.964). Therefore, it is concluded that the automated SPR platform can be applied to quantify 3-NT in biological samples with its sensitivity, accuracy, and real-timing.


Assuntos
Técnicas Biossensoriais , Ressonância de Plasmônio de Superfície , Tirosina/análogos & derivados , Anticorpos/imunologia , Antígenos/imunologia , Reações Cruzadas , Humanos , Imunoensaio/métodos , Limite de Detecção , Ovalbumina/imunologia , Tirosina/imunologia , Tirosina/urina
9.
J Pharm Biomed Anal ; 158: 431-437, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-29945060

RESUMO

In this paper, a simple, rapid and high-throughput fluorescence polarization immunoassay (FPIA) based on polyclonal antibodies (PAb) is described for the determination of glycocholic acid (GCA) in human urine. Three fluorescein-labeled GCA (tracers) with different structures and spacer bridges were synthesized and purified by thin-layer chromatography (TLC). The structure effect of tracers on the assay was investigated and the sensitivity of best tracer in the optimized FPIA demonstrated an IC50 value of 306 ng/mL. The working range of FPIA was 36 ∼ 2 600 ng/mL and the limit of detection (LOD) was 9 ng/mL. The developed FPIA was time-saving that could be completed within 10 min. Human urine samples spiked with GCA were analyzed by this method, followed by confirmation with commercial enzyme immunoassay analysis (EIA). Excellent recoveries and correlation between these two methods were observed (R2 = 0.996), suggesting the developed FPIA could be applied to screening of GCA in human urine samples without complicated cleanup.


Assuntos
Biomarcadores Tumorais/urina , Imunoensaio de Fluorescência por Polarização/métodos , Ácido Glicocólico/urina , Ensaios de Triagem em Larga Escala/métodos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/fisiopatologia , Carcinoma Hepatocelular/urina , Fluoresceína/química , Imunoensaio de Fluorescência por Polarização/instrumentação , Corantes Fluorescentes/química , Voluntários Saudáveis , Ensaios de Triagem em Larga Escala/instrumentação , Humanos , Limite de Detecção , Fígado/fisiopatologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/fisiopatologia , Neoplasias Hepáticas/urina , Sensibilidade e Especificidade , Fatores de Tempo
10.
Analyst ; 143(9): 2057-2065, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29629470

RESUMO

Glycocholic acid (GCA) has been identified as a novel selective and sensitive biomarker for hepatocellular carcinoma (HCC). In this work, a recombinant antibody, scFv-G11, which was shown previously to have selective reactivity for GCA, was labeled with biotin using a chemical and an enzymatic method, respectively. The enzymatic method proved superior giving sensitive scFv-biotin preparations. Based on biotinylated scFv against GCA and a biotin-streptavidin system for signal amplification, an indirect competitive biotin-streptavidin-amplified enzyme-linked immunosorbent assay (BA-ELISA) has been established for the sensitive and rapid detection of GCA. Several physiochemical factors that influenced assay performance, such as organic cosolvent, ionic strength, and pH, were studied. Under the optimized conditions, the indirect competitive BA-ELISA based on the obtained biotinylated scFv antibodies indicated that the average concentration required for 50% inhibition of binding (IC50) and the limit of detection (LOD) for GCA were 0.42 µg mL-1 and 0.07 µg mL-1, respectively, and the linear response range extended from 0.14 to 1.24 µg mL-1. Cross-reactivity of biotinylated scFv antibodies with various bile acid analogues was below 1.89%, except for taurocholic acid. The recoveries of GCA from urine samples via this indirect competitive BA-ELISA ranged from 108.3% to 131.5%, and correlated well with liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS), which indicated the accuracy and reliability of biotinylated scFv-based ELISA in the detection of GCA in urine samples. This study also demonstrates the broad utility of scFv for the development of highly sensitive immunoassays.


Assuntos
Ensaio de Imunoadsorção Enzimática , Ácido Glicocólico/análise , Anticorpos de Cadeia Única/química , Biotina , Carcinoma Hepatocelular , Ácido Glicocólico/urina , Humanos , Reprodutibilidade dos Testes
11.
Bioorg Med Chem Lett ; 28(2): 85-93, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29233651

RESUMO

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Desenho de Drogas , Propanóis/farmacologia , Receptores do Ácido Retinoico/agonistas , Receptores de Esteroides/agonistas , Sulfonamidas/farmacologia , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Receptores X do Fígado/agonistas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Propanóis/síntese química , Propanóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
12.
Oncotarget ; 8(54): 93051-93062, 2017 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-29190977

RESUMO

Peroxisome proliferator-activated receptor-α (PPAR-α), a lipid activated transcription factor of nuclear hormone receptor superfamily, can relieve pain through a rapid-response mechanism. However, little is known about the underlying mechanism. Herein, we report that PPAR-α activation acutely inhibits the functional activity of acid-sensing ion channels (ASICs), key sensors for extracellular protons, in rat dorsal root ganglion (DRG) neurons. Pre-application of PPAR-α agonist GW7647 for 2 min decreased the amplitude of proton-gated currents mediated by ASICs in a concentration-dependent manner. GW7647 shifted the concentration-response curve for proton downwards, with a decrease of 36.9 ± 2.3% in the maximal current response to proton. GW7647 inhibition of proton-gated currents can be blocked by GW6471, a selective PPAR-α antagonist. Moreover, PPAR-α activation decreased the number of acidosis-evoked action potentials in rat DRG neurons. Finally, peripheral administration of GW7647 dose-dependently relieved nociceptive responses to injection of acetic acid in rats. These results indicated that activation of peripheral PPAR-α acutely inhibited functional activity of ASICs in a non-genomic manner, which revealed a novel mechanism underlying rapid analgesia through peripheral PPAR-α.

13.
Phys Chem Chem Phys ; 19(48): 32708-32714, 2017 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-29199287

RESUMO

Lithium-sulfur (Li-S) batteries have attracted increasing attention due to their high theoretical capacity, being a promising candidate for portable electronics, electric vehicles and large-scale energy storage. The interactions of bilayer structured graphitic C3N4 (bi-C3N4) with S8, lithium polysulfides (LiPSs), 1,3-dioxolane, 1,2-dimethoxyethane and tetrahydrofuran ether-based solvents have been studied using first-principles calculations. It has been found that the (micropore-scale) interlayer of bi-C3N4 shows intimate contact and strong binding with S8 and LiPSs due to the formation of chemical Li-N bonds. The incorporation of soluble LiPSs by the wrinkled layers of bi-C3N4 with 5.5-7.2 Å interlayer pores can suppress the shuttling effect. The interlayer ultramicropores with interlayer distances of <4 Å can accommodate the small Li2S2 and Li2S molecules, and impede the irreversible reaction between the solvents and the LiPSs. The calculated energy gap of bi-C3N4 decreases to be narrow during lithiation. Our results can provide a guideline for promoting the electrochemical performance of microporous g-C3N4/sulfur composites for Li-S batteries.

14.
Anal Chem ; 89(20): 11091-11097, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-28942640

RESUMO

Glycocholic acid (GCA) is an important metabolite of bile acids, whose urine levels are expected to be a specific diagnostic biomarker for hepatocellular carcinoma (HCC). A high-throughput immunoassay for determination of GCA would be of significant advantage and useful for primary diagnosis, surveillance, and early detection of HCC. Single-chain variable fragment (scFv) antibodies have several desirable characteristics and are an attractive alternative to traditional antibodies for the immunoassay. Because chicken antibodies possess single heavy and light variable functional domains, they are an ideal framework for simplified generation of recombinant antibodies for GCA detection. However, chicken scFvs have rarely been used to detect GCA. In this study, a scFv library was generated from chickens immunized with a GCA hapten coupled to bovine serum albumin (BSA), and anti-GCA scFvs were isolated by a phage-displayed method. Compared to the homologous coating antigen, use of a heterologous coating antigen resulted in about an 85-fold improvement in sensitivity of the immunoassay. This assay, under optimized conditions, had a linear range of 0.02-0.18 µg/mL, with an IC50 of 0.06 µg/mL. The assay showed negligible cross-reactivity with various related bile acids, except for taurocholic acid. The detection of GCA from spiked human urine samples ranged from 86.7% to 123.3%. These results, combined with the advantages of scFv antibodies, indicated that a chicken scFv-based enzyme-linked immunosorbent assay is a suitable method for high-throughput screening of GCA in human urine.


Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Ácido Glicocólico/análise , Anticorpos de Cadeia Única/imunologia , Sequência de Aminoácidos , Animais , Técnicas de Visualização da Superfície Celular , Galinhas , Reações Cruzadas , Ácido Glicocólico/imunologia , Ácido Glicocólico/urina , Humanos , Biblioteca de Peptídeos , Alinhamento de Sequência
15.
Medchemcomm ; 8(4): 725-729, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108791

RESUMO

Recently, our research group reported the identification of prodrug amino-alcohol 2 as a potent and efficacious S1P1 receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya 1), whose active phosphate metabolite is an S1P1 full agonist, in terms of pulmonary and cardiovascular safety. S1P1 partial agonist 2, however, has a long half-life in rodents and was projected to have a long half-life in humans. The purpose of this communication is to disclose highly potent partial agonists of S1P1 with shorter half-lives relative to the clinical compound 2. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.

16.
J Med Chem ; 59(24): 11138-11147, 2016 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-28002964

RESUMO

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Naftalenos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade
17.
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 Drogas , 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
18.
J Med Chem ; 59(13): 6248-64, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27309907

RESUMO

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P1 receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P1 agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P1 agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P3 are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).


Assuntos
Etanolamina/química , Etanolamina/farmacologia , Linfócitos/efeitos dos fármacos , Receptores de Lisoesfingolipídeo/agonistas , Animais , Artrite/tratamento farmacológico , Cães , Encefalomielite Autoimune Experimental/tratamento farmacológico , Etanolamina/farmacocinética , Etanolamina/uso terapêutico , Feminino , Haplorrinos , Humanos , Contagem de Linfócitos , Linfócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 26(10): 2470-2474, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27055941

RESUMO

The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Relação Estrutura-Atividade , Administração Oral , Animais , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Contagem de Linfócitos , Masculino , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/agonistas
20.
Zhongguo Dang Dai Er Ke Za Zhi ; 18(4): 340-4, 2016 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-27097580

RESUMO

OBJECTIVE: To preliminarily investigate the relationship between serum apelin level and pulmonary artery pressure in children with congenital heart disease. METHODS: One hundred and twenty-six children with congenital heart disease undergoing surgical treatment were enrolled as subjects. The serum level of apelin was determined before surgery and at 7 days after surgery. The ratio of pulmonary artery systolic pressure to aortic systolic pressure (Pp/Ps) was calculated before extracorporeal circulation. According to the Pp/Ps value, patients were classified into non-pulmonary arterial hypertension (PAH) group, mild PAH group, moderate PAH group, and severe PAH group. Pulmonary artery mean pressure was estimated by echocardiography at 7 days after surgery. RESULTS: The non-PAH group had the highest serum level of apelin before and after surgery, followed by the mild PAH group, moderate PAH group, and severe PAH group (P<0.05). All groups had significantly increased serum levels of apelin at 7 days after surgery (P<0.05). The serum level of apelin was negatively correlated with pulmonary artery pressure before surgery (r=-0.51, P<0.05) and at 7 days after surgery (r=-0.54, P<0.05). CONCLUSIONS: The decrease in serum apelin level is associated with the development of pulmonary hypertension in children with congenital heart disease. The significance of serum apelin in predicting the development and degree of pulmonary hypertension in children with congenital heart disease deserves further studies.


Assuntos
Cardiopatias Congênitas/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Artéria Pulmonar/fisiopatologia , Apelina , Pressão Sanguínea , Pré-Escolar , Feminino , Cardiopatias Congênitas/sangue , Humanos , Hipertensão Pulmonar/sangue , Lactente , Masculino
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