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1.
Eur J Obstet Gynecol Reprod Biol ; 233: 84-92, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30580229

RESUMO

OBJECTIVE: The objective is to systematically review and synthesize the literature on the efficacy with two different cryopreservation methods used for human spermatozoa and evaluate whether vitrification protocol and quality of sperm influence effect estimates. DESIGN: The following electronic databases were searched up to September 2017: Pubmed, Embase and Web of Science. The search strategy used the following the relevant medical subject heading (MeSH) terms, keywords, and word variants for: sperm parameters, conventional freezing, and vitrification. Queries were limited to those involving humans. Randomized controlled trials (RCTs) that published in English languages were considered eligible. Studies and references were included if they reported total motility, progressive motility, morphology, or DNA fragmentation index (DFI) for vitrified or conventional cryopreserved human spermatozoa. Patients recruited in RCTs considering sperm vitrification as one of the experimental arms and conventional freezing (including slow freezing or vapor fast freezing) sperm control as the other. Studies that had high risks of allocation concealment were excluded when performing sensitivity analysis. We specified 2 subgroup variables, including vitrification protocol and quality of spermatozoa cryopreserved, to investigate sources of heterogeneity. A meta-analysis was performed using a random effects (I2 > 50%) or fixed effects (I2 < 50%) model to calculate weighted mean differences (MD) and 95% CI. RESULT(S): The search yielded a total of 2428 articles and 13 RCTs were included for analysis. They involved 486 vitrified and 486 conventional cryopreserved sperm samples. Four sperm parameters were reported as mean differences and based on adjusted estimates in all included studies. Meta-analysis of these studies showed significantly higher total motility [weighted mean differences (WMD) 6.98; 95% confidence interval (CI) 2.94; 11.02; P < 0.0001] and progressive motility [WMD 4.59; 95% CI 0.78; 8.39; P = 0.02] of past-thawed sperm following vitrification compared with conventional freezing methods. However, DNA fragmentation index (DFI) [WMD -1.18; 95% CI -2.81; 0.45; P = 0.16] and morphology [WMD 0.11; 95% CI -0.42; 0.63; P = 0.69] of past-thawed sperm are similar between two freezing groups. Subgroup analysis shown that the vitrification protocol and quality of spermatozoa are potential risk factors for the efficacy of vitrification. Higher past-thawed sperm parameters following the cryoprotectants-free (CPAs-free) vitrification were observed, as well as a lower past-thawed sperm parameters with the cryoprotectants-presence (CPAs-presence) vitrification, which could reflect the CPAs related cytotoxicity. Meanwhile, vitrification had higher ability in preservation of high quality of spermatozoa compared with vitrification of low quality spermatozoa. CONCLUSION(S): According to the results of present meta-analysis, vitrification is superior to conventional freezing methods in preservation of spermatozoa, regarding total and progressive motility. However, the efficacy of vitrification is influence by using different vitrification protocol and cryopreservation of different quality spermatozoa. It is must emphasized that the results of present meta-analysis is limited by the small number of studies of variable vitrification protocol. Further well conducted studies are required to confirm the efficacy of vitrification in cryopreservation of spermatozoa, in addition, allow the examination of the two cryopreservation methods in terms of pregnancy achievement and determination of the role of clinical variable on efficacy of vitrification.


Assuntos
Criopreservação/métodos , Preservação do Sêmen/métodos , Espermatozoides , Vitrificação , Fragmentação do DNA , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Motilidade Espermática
2.
Toxicol Ind Health ; : 748233718796347, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30360701

RESUMO

Formaldehyde (FA), a ubiquitous environmental contaminant, has long been suspected of causing lung injury. However, the molecular and cellular mechanisms underlying this phenomenon remain elusive. The aim of this study was to elucidate the role of autophagy in lung injury induced by FA inhalation. In this study, lung weight coefficient, interleukin 8 in bronchoalveolar fluid, and histopathological examination were used to evaluate the lung injury. Moreover, electron microscopy, Western blotting for the ratio of LC3-II/LC3-I were used to detect autophagy in lung tissues. Our results indicated that the lung toxicity of FA inhalation is dose dependent. Lung weight coefficient, inflammatory response, and histopathological structure in the 0.5 mg/m3 FA exposure group showed no obvious changes compared with the control. However, exposure to 5 and 10 mg/m3 FA produced lung injury including pulmonary edema, histological changes, and inflammatory responses. Furthermore, the alterations of autophagy correlated with lung injury. Taken together, these data indicate that FA exposure triggers autophagy of alveolar epithelial cells, which might play a pivotal role in lung injury.

3.
Bioorg Med Chem Lett ; 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348490

RESUMO

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.

4.
J Breast Cancer ; 21(3): 251-258, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30275853

RESUMO

Purpose: Multidrug resistance (MDR) remains a major obstacle in the treatment of triple-negative breast cancer (TNBC) with conventional chemotherapeutic agents. A previous study demonstrated that hsa-miRNA-143-3p plays a vital role in drug resistance of TNBC. Downregulation of hsa-miRNA-143-3p upregulated the expression of its target protein cytokine-induced apoptosis inhibitor 1 (CIAPIN1) in order to activate MDR, while upregulation of hsa-miRNA-143-3p effectively enhances the sensitivity of drug-resistant TNBC cells to chemotherapeutics. The present study aimed to further verify these findings in vivo. Methods: We established a hypodermic tumor nude mice model using paclitaxel-resistant TNBC cells. We expressed ectopic hsa-miRNA-143-3p under the control of a breast cancer-specific human mammaglobin promoter that guided the efficient expression of exogenous hsa-miRNA-143-3p only in breast cancer cells. Thereafter, we overexpressed hsa-miRNA-143-3p in xenografts using a recombinant virus system and quantified the expression of hsa-miRNA-143-3p, CIAPIN1 protein, and proteins encoded by related functional genes by western blot. Results: We successfully completed the prospective exploration of the intravenous virus injection pattern from extensive expression to targeted expression. The overexpression of hsa-miRNA-143-3p significantly alleviated chemoresistance of TNBC by inhibiting viability. In addition, we observed that the expression of CIAPIN1 as a hsa-miRNA-143-3p target protein was remarkably decreased. Conclusion: We partly illustrated the mechanism underlying the hsa-miRNA-143-3p/CIAPIN1 drug resistance pathway. HsamiRNA-143-3p as a tumor suppressive microRNA may be a novel target to effectively reverse MDR of TNBC in vivo.

5.
J Med Chem ; 60(12): 4932-4948, 2017 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-28537398

RESUMO

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Actinas/antagonistas & inibidores , Adamantano/administração & dosagem , Adamantano/química , Adamantano/farmacologia , Administração Oral , Animais , Azetidinas/administração & dosagem , Azetidinas/química , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Feminino , Meia-Vida , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Camundongos Obesos , Ratos , Relação Estrutura-Atividade
6.
J Org Chem ; 81(19): 9499-9506, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27615449

RESUMO

A one-step synthesis of Fmoc-protected aryl/heteroaryl-substituted phenylalanines (Bip derivatives) using the nonaqueous palladium-catalyzed Suzuki-Miyaura cross-coupling (SMC) reaction of Fmoc-protected bromo- or iodophenylalanines is reported. This protocol allows for the direct formation of a variety of unnatural biaryl-containing amino acids in good to excellent yield, which can be readily used in subsequent Fmoc solid-phase peptide synthesis. The synthetic utility of this method is also demonstrated by the SMC reaction of bromophenylalanine-containing tripeptides.

7.
Am J Transl Res ; 8(7): 3214-26, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27508043

RESUMO

OBJECTIVES: Microbiota has been suggested in promoting chronic inflammation in human tissues which, in turn, promotes tumor development. This study tests a hypothesis that high-risk human papillomavirus (HR-HPV) infection may correlate with proinflammatory Stat3 signaling activities and IL-17 levels in breast cancer (BC) patients. MATERIALS AND METHODS: This study examined HPV infection by GenChip technology, constitutively active Stat3 (p-Stat3) and IL-17 levels by immunohistochemistry (IHC) using specific antibodies in 379 BC patients, together with 245 paired adjacent breast adenosis (ABA) tissues and 100 unrelated breast adenosis (BA) tissues. RESULTS: We obtained four major findings: (1) HR-HPV16/18 infections existed in 10.5% (34/325) of BC issues, higher than control BA tissues (4%, 4/100, P = 0.047). (2) Using IHC methodology, BC tissues showed more overactive p-Stat3 (2+/3+, 38.5%, 146/379) than ABA tissues (27.3%, 67/245, P < 0.001); similarly, BC also had more tissues overexpressing IL-17 (2+/3+, 61.5%, 233/379) than ABA tissues (51.8%, 127/245, P < 0.001). (3) High levels (2+/3+) of both active p-Stat3 and IL-17 correlated with poor differentiation and lymph nodal metastasis in BC (both with P < 0.05), but not with patients' prognosis. (4) HR-HPV infections correlated with both active p-Stat3 (P = 0.018) and its downstream IL-17 levels (P = 0.021) in BC tissues. CONCLUSION: There may be a possible tri-lateral relationship among HPV infection, constitutive Stat3 activity and IL-17 level, whose collaborations could orchestrate a proinflammatory microenvironment in breast tissues by which promote carcinogenesis and/or facilitate progression of breast cancer.

8.
ACS Med Chem Lett ; 7(6): 590-4, 2016 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-27326332

RESUMO

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

9.
Bioorg Med Chem ; 24(10): 2257-72, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27073051

RESUMO

Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.


Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Fator XIa/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Administração Oral , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Coagulação Sanguínea/efeitos dos fármacos , Cristalografia por Raios X , Cães , Fator XIa/metabolismo , Humanos , Modelos Moleculares , Fenilcarbamatos/administração & dosagem , Fenilcarbamatos/química , Fenilcarbamatos/farmacocinética , Fenilcarbamatos/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética
10.
Ying Yong Sheng Tai Xue Bao ; 27(12): 4052-4058, 2016 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-29704367

RESUMO

As a key species in the Antarctic ecosystem, the spatial distribution of Antarctic krill (thereafter krill) often tends to present aggregation characteristics, which therefore reflects the spatial patterns of krill fishing operation. Based on the fishing data collected from Chinese krill fishing vessels, of which vessel A was professional krill fishing vessel and Vessel B was a fishing vessel which shifted between Chilean jack mackerel (Trachurus murphyi) fishing ground and krill fishing ground. In order to explore the characteristics of spatial distribution pattern and their ecological effects of two obvious different fishing fleets under a high and low nominal catch per unit effort (CPUE), from the viewpoint of spatial point pattern, the present study analyzed the spatial distribution characteristics of krill fishery in the northern Antarctic Peninsula from three aspects: (1) the two vessels' point pattern characteristics of higher CPUEs and lower CPUEs at different scales; (2) correlation of the bivariate point patterns between these points of higher CPUE and lower CPUE; and (3) correlation patterns of CPUE. Under the analysis derived from the Ripley's L function and mark correlation function, the results showed that the point patterns of the higher/lo-wer catch available were similar, both showing an aggregation distribution in this study windows at all scale levels. The aggregation intensity of krill fishing was nearly maximum at 15 km spatial scale, and kept stably higher values at the scale of 15-50 km. The aggregation intensity of krill fishery point patterns could be described in order as higher CPUE of vessel A > lower CPUE of vessel B >higher CPUE of vessel B > higher CPUE of vessel B. The relationship of the higher and lo-wer CPUEs of vessel A showed positive correlation at the spatial scale of 0-75 km, and presented stochastic relationship after 75 km scale, whereas vessel B showed positive correlation at all spatial scales. The point events of higher and lower CPUEs were synchronized, showing significant correlations at most of spatial scales because of the dynamics nature and complex of krill aggregation patterns. The distribution of vessel A's CPUEs was positively correlated at scales of 0-44 km, but negatively correlated at the scales of 44-80 km. The distribution of vessel B's CPUEs was negatively correlated at the scales of 50-70 km, but no significant correlations were found at other scales. The CPUE mark point patterns showed a negative correlation, which indicated that intraspecific competition for space and prey was significant. There were significant differences in spatial point pattern distribution between vessel A with higher fishing capacity and vessel B with lower fishing capacity. The results showed that the professional krill fishing vessel is suitable to conduct the analysis of spatial point pattern and scientific fishery survey.


Assuntos
Euphausiacea , Pesqueiros , Animais , Regiões Antárticas , Ecologia , Ecossistema
11.
J Med Chem ; 58(22): 9010-26, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26524347

RESUMO

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.


Assuntos
Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Benzilaminas/síntese química , Benzilaminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Anticolesterolemiantes/farmacocinética , Aterosclerose/tratamento farmacológico , Benzamidas/farmacocinética , Benzilaminas/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Colesterol/metabolismo , HDL-Colesterol/sangue , Cricetinae , Citocromo P-450 CYP11B2/antagonistas & inibidores , Cães , Descoberta de Drogas , Humanos , Macaca fascicularis , Masculino , Mesocricetus , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley
12.
Bioorg Med Chem Lett ; 25(14): 2793-9, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26022839

RESUMO

Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.


Assuntos
Fármacos Antiobesidade/química , Pirazóis/química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Meia-Vida , Humanos , Obesidade/tratamento farmacológico , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Perda de Peso/efeitos dos fármacos
13.
PLoS One ; 10(2): e0118391, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25706309

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a major burden of public health and healthcare worldwide. Microbiota has been suggested in promoting chronic inflammation in the intestine which, in turn, promotes tumor development. This study focuses on possible correlations of human papillomavirus (HPV) infection with proinflammatory Stat3 signaling activities and the resulting levels of its downstream proinflammatory cytokine IL-17 in CRC patients. METHODS: HPV was examined using HPV Genotyping Chip technology and constitutively active Stat3 (p-Stat3) and IL-17 levels were tested using immunohistochemistry (IHC) in paraffin-embedded cancerous and adjacent normal tissues (ANT) from a cohort of 95 CRC patients. Correlation analyses were performed between HPV infection and clinicopathological characteristics, Stat3 activities and IL-17 levels among these CRC patients. RESULTS: Three major findings were observed: (1) HPV infection existed in a high rate of CRC cases (48.4%, 46/95), of which 45 cases (45/46, 97.8%) were high-risk HPV16-positive and only one case was HPV53-positive. (2) HPV infection correlated with poorer clinical stages (III+IV) of CRC. (3) HPV infection strongly correlated with both constitutively higher Stat3 activities (P<0.01) and higher IL-17 levels (P<0.01) only in CRC tissues but not in ANT tissues. CONCLUSIONS: HPV infection is common in CRC patients suggesting potentially preventive effectiveness of HPV vaccination among high-risk young individuals. We have for the first time revealed a tri-lateral relationship among HPV infection, constitutive Stat3 activity and IL-17 level, whose collaborative act may orchestrate a proinflammatory microenvironment in the colorectum that, in turn, may promote carcinogenesis and possibly facilitate progression of CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Interleucina-17/metabolismo , Infecções por Papillomavirus/metabolismo , Fator de Transcrição STAT3/metabolismo , China , Neoplasias Colorretais/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/complicações
14.
Bioorg Med Chem Lett ; 25(6): 1196-205, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25686852

RESUMO

The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.


Assuntos
Hipoglicemiantes/síntese química , PPAR alfa/agonistas , PPAR gama/agonistas , Pirrolidinas/química , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Drogas , Feminino , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Ligantes , Camundongos , Camundongos Obesos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/uso terapêutico , Estereoisomerismo , Relação Estrutura-Atividade , Triglicerídeos/sangue
15.
Int J Clin Exp Med ; 8(11): 21635-40, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26885117

RESUMO

BACKGROUND: Macrophage apoptosis triggered by endoplasmic reticulum (ER) stress contributes much to atherosclerosis, especially plaque vulnerability. Activating transcription factor 4 (ATF4)-CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP)-Tribbles 3 (TRIB3) pathway is closely related to the ER stress. This study aimed to investigate the effect of atorvastatin on the ATF4-CHOP-TRIB3 pathway. METHODS: Forty-seven patients were randomized into 80-mg and 20-mg atorvastatin group. Follow-up was performed at weeks 6 and 12, and complete blood chemistry, lipid assay and detection of 5 target genes (tumor protein 53, ATF4, C/EBP, CHOP and TRIB3) in monocytes/macrophages were conducted. Furthermore, the interaction between dosage and duration of therapy was evaluated. RESULTS: After 12-week therapy, patients in both groups experienced significant reductions in ATF4 (P=0.038) and C/EBP (P=0.003) expressions. Tumor protein 53 (P=0.015) and TRIB3 (P=0.045) expressions increased markedly in 80-mg atorvastatin group. However, there was no significant difference in CHOP expression at three time-points and between atorvastatin groups. Moreover, there was no interaction between dosage and duration of therapy. CONCLUSIONS: Atorvastatin has an effect on ER stress through ATF4-CHOP pathway. Atorvastatin at a high dose is more likely to increase TRIB3 expression, but this warrants further investigation.

16.
J Med Chem ; 57(18): 7499-508, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25208139

RESUMO

G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic ß-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.


Assuntos
Descoberta de Drogas , Hipoglicemiantes/farmacologia , Terapia de Alvo Molecular , Piridonas/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Sulfonas/farmacologia , Animais , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Drogas , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Masculino , Camundongos , Modelos Moleculares , Conformação Proteica , Piridonas/química , Piridonas/farmacocinética , Piridonas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/química , Sulfonas/química , Sulfonas/farmacocinética , Sulfonas/uso terapêutico
17.
ChemMedChem ; 9(10): 2327-43, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24989964

RESUMO

Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y1 antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.


Assuntos
Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ureia/análogos & derivados , Animais , Humanos , Espectroscopia de Ressonância Magnética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Espectrometria de Massas por Ionização por Electrospray , Ureia/farmacocinética , Ureia/farmacologia
18.
Bioorg Med Chem Lett ; 24(2): 654-60, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24360604

RESUMO

A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11ß-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11ß-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11ß-HSD1 with a favorable development profile.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/síntese química , Tetrazóis/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adamantano/farmacologia , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Camundongos Transgênicos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Estrutura Secundária de Proteína , Relação Estrutura-Atividade , Tetrazóis/farmacologia
19.
Zhonghua Yan Ke Za Zhi ; 49(4): 340-4, 2013 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-23900094

RESUMO

OBJECTIVE: To compare the intraocular pressure (IOP) lowering effect of 0.004% travoprost and 2% carteolol in patients with ocular hypertension (OHT) after laser peripheral iridotomy (LPI) or trabeculectomy in primary angle-closure glaucoma (PACG). METHODS: Clinical case control trial. 52 consecutive PACG patients (52 eyes) with IOP > 21 mm Hg (1 mm Hg = 0.133 kPa) after LPI or trabeculectomy were enrolled. 24 patients received topical application of 0.004% travoprost (once daily) and 28 received 2% carteolol (twice daily). IOP lowering effect of travoprost and carteolol before and after treatment was measured by Goldmann tonometer and compared using t-test. The relationship of IOP lowering effect and the degree of angle open was performed by gonioscope and analyzed using Spearman rank correlation. RESULTS: Compared with pre-treatment, the IOP was significantly reduced in 24 patients (24 eyes) in 0.004% travoprost group [pre-treatment: (24.67 ± 3.08) mm Hg, post-treatment: (18.58 ± 2.71) mm Hg; t = 6.600, P < 0.05], while significantly reduced in 28 patients (28 eyes) received 2% carteolol [pre-treatment: (23.57 ± 1.60) mm Hg, post-treatment: (19.57 ± 1.60) mm Hg; t = 5.130, P < 0.05]. 0.004% travoprost group is more significant in both quantity and percentage of IOP lowering than 2% carteolol (t = 2.533, 2.532; P < 0.05). There was no correlation between the IOP lowering effect and the degree of angle open in both groups (0.004% travoprost r = 0.145, 0.009; P > 0.05; 2% carteolol r = 0.090, 0.183, P > 0.05). CONCLUSIONS: Both of 0.004% travoprost and 2% carteolol reduce IOP in patients with OHT after LPI or trabeculectomy in PACG. 0.004% travoprost is more effective than 2% carteolol in IOP lowering. However, the decrease of IOP is not acted through the alteration of anterior chamber angle in both study groups.


Assuntos
Carteolol/uso terapêutico , Cloprostenol/análogos & derivados , Glaucoma de Ângulo Fechado/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Carteolol/administração & dosagem , Cloprostenol/administração & dosagem , Cloprostenol/uso terapêutico , Feminino , Glaucoma de Ângulo Fechado/fisiopatologia , Glaucoma de Ângulo Fechado/cirurgia , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/etiologia , Complicações Pós-Operatórias , Trabeculectomia , Travoprost
20.
J Med Chem ; 56(18): 7343-57, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-23964740

RESUMO

Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.


Assuntos
Acetamidas/química , Acetamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Drogas , Pirróis/química , Pirróis/farmacologia , Acetamidas/síntese química , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Domínio Catalítico , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/síntese química , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Modelos Moleculares , Pirróis/síntese química , Especificidade por Substrato
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