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Schistosomiasis, a parasite infectious disease caused by Schistosoma japonicum, often leads to egg granuloma and fibrosis due to the inflammatory reaction triggered by egg antigens released in the host liver. This study focuses on the role of the egg antigens CP1412 protein of S. japonicum (SjCP1412) with RNase activity in promoting liver fibrosis. In this study, the recombinant egg ribonuclease SjCP1412, which had RNase activity, was successfully prepared. By analysing the serum of the population, it has been proven that the anti-SjCP1412 IgG in the serum of patients with advanced schistosomiasis was moderately correlated with liver fibrosis, and SjCP1412 may be an important antigen associated with liver fibrosis in schistosomiasis. In vitro, the rSjCP1412 protein induced the human liver cancer cell line Hep G2 and liver sinusoidal endothelial cells apoptosis and necrosis and the release of proinflammatory damage-associated molecular patterns (DAMPs). In mice infected with schistosomes, rSjCP1412 immunization or antibody neutralization of SjCP1412 activity significantly reduced cell apoptosis and necroptosis in liver tissue, thereby reducing inflammation and liver fibrosis. In summary, the SjCP1412 protein plays a crucial role in promoting liver fibrosis during schistosomiasis through mediating the liver cells apoptosis and necroptosis to release DAMPs inducing an inflammatory reaction. Blocking SjCP1412 activity could inhibit its proapoptotic and necrotic effects and alleviate hepatic fibrosis. These findings suggest that SjCP1412 may be served as a promising drug target for managing liver fibrosis in schistosomiasis japonica.
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Schistosoma japonicum , Esquistossomose Japônica , Humanos , Camundongos , Animais , Esquistossomose Japônica/complicações , Esquistossomose Japônica/parasitologia , Ribonucleases/metabolismo , Ribonucleases/farmacologia , Células Endoteliais , Cirrose Hepática/parasitologia , Cirrose Hepática/patologia , Fígado/patologia , Inflamação/patologiaRESUMO
Inhibition of monoacylglycerol transferase 2 (MGAT2) has recently emerged as a potential therapeutic strategy for the treatment of metabolic diseases such as obesity, diabetes and non-alcoholic steatohepatitis (NASH). Metabolism studies with our clinical lead (1) suggested variability in in vitro glucuronidation rates in liver microsomes across species, which made projection of human doses challenging. In addition, the observation of deconjugation of the C3-C4 double bond in the dihydropyridinone ring of 1 in solution had the potential to complicate its clinical development. This report describes our lead optimization efforts in a novel pyridinone series, exemplified by compound 33, which successfully addressed both of these potential issues.
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Doenças Metabólicas , Monoglicerídeos , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/química , Obesidade/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológicoRESUMO
GPR40 AgoPAMs are highly effective antidiabetic agents that have a dual mechanism of action, stimulating both glucose-dependent insulin and GLP-1 secretion. The early lipophilic, aromatic pyrrolidine and dihydropyrazole GPR40 AgoPAMs from our laboratory were highly efficacious in lowering plasma glucose levels in rodents but possessed off-target activities and triggered rebound hyperglycemia in rats at high doses. A focus on increasing molecular complexity through saturation and chirality in combination with reducing polarity for the pyrrolidine AgoPAM chemotype resulted in the discovery of compound 46, which shows significantly reduced off-target activities as well as improved aqueous solubility, rapid absorption, and linear PK. In vivo, compound 46 significantly lowers plasma glucose levels in rats during an oral glucose challenge yet does not demonstrate the reactive hyperglycemia effect at high doses that was observed with earlier GPR40 AgoPAMs.
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Glicemia , Hiperglicemia , Ratos , Animais , Receptores Acoplados a Proteínas G , Peptídeo 1 Semelhante ao Glucagon , Hipoglicemiantes/farmacologia , Pirrolidinas/farmacologia , Pirrolidinas/química , InsulinaRESUMO
PURPOSE: Short- and long-term complications of gestational diabetes mellitus (GDM) involving pregnancies and offspring warrant the development of an effective individualized risk prediction model to reduce and prevent GDM together with its associated co-morbidities. The aim is to use machine learning (ML) algorithms to study data gathered throughout the first trimester in order to predict GDM. METHODS: Two independent cohorts with forty-five features gathered through first trimester were included. We constructed prediction models based on three different algorithms and traditional logistic regression, and deployed additional two ensemble algorithms to identify the importance of individual features. RESULTS: 4799 and 2795 pregnancies were included in the Xinhua Hospital Chongming branch (XHCM) and the Shanghai Pudong New Area People's Hospital (SPNPH) cohorts, respectively. Extreme gradient boosting (XGBoost) predicted GDM with moderate performance (the area under the receiver operating curve (AUC) = 0.75) at pregnancy initiation and good-to-excellent performance (AUC = 0.99) at the end of the first trimester in the XHCM cohort. The trained XGBoost showed moderate performance in the SPNPH cohort (AUC = 0.83). The top predictive features for GDM diagnosis were pre-pregnancy BMI and maternal abdominal circumference at pregnancy initiation, and FPG and HbA1c at the end of the first trimester. CONCLUSION: Our work demonstrated that ML models based on the data gathered throughout the first trimester achieved moderate performance in the external validation cohort.
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A new SEK15-derived polyketide compound, strepolyketide D (1), was isolated from salt-lake-derived Streptomyces sp. DBC5, together with two known analogues (2-3). Their structures were elucidated based on spectroscopic analysis of IR, MS, 1 D and 2 D NMR. Compound 2 elicited moderate antioxidation with IC50 value of 39.26 µg/ml. The results of the study revealed that salt-lake actinomycetes of Lake Dabancheng appear to have immense potential as a source of polyketide compounds.
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Policetídeos , Streptomyces , Streptomyces/química , Lagos , Espectroscopia de Ressonância MagnéticaRESUMO
Cervical cancer is the most common cancer among women worldwide. The diagnosis and classification of cancer are extremely important, as it influences the optimal treatment and length of survival. The objective was to develop and validate a diagnosis system based on convolutional neural networks (CNN) that identifies cervical malignancies and provides diagnostic interpretability. A total of 8496 labeled histology images were extracted from 229 cervical specimens (cervical squamous cell carcinoma, SCC, n = 37; cervical adenocarcinoma, AC, n = 8; nonmalignant cervical tissues, n = 184). AlexNet, VGG-19, Xception, and ResNet-50 with five-fold cross-validation were constructed to distinguish cervical cancer images from nonmalignant images. The performance of CNNs was quantified in terms of accuracy, precision, recall, and the area under the receiver operating curve (AUC). Six pathologists were recruited to make a comparison with the performance of CNNs. Guided Backpropagation and Gradient-weighted Class Activation Mapping (Grad-CAM) were deployed to highlight the area of high malignant probability. The Xception model had excellent performance in identifying cervical SCC and AC in test sets. For cervical SCC, AUC was 0.98 (internal validation) and 0.974 (external validation). For cervical AC, AUC was 0.966 (internal validation) and 0.958 (external validation). The performance of CNNs falls between experienced and inexperienced pathologists. Grad-CAM and Guided Gard-CAM ensured diagnoses interpretability by highlighting morphological features of malignant changes. CNN is efficient for histological image classification tasks of distinguishing cervical malignancies from benign tissues and could highlight the specific areas of concern. All these findings suggest that CNNs could serve as a diagnostic tool to aid pathologic diagnosis.
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Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/diagnóstico por imagem , Redes Neurais de Computação , Colo do ÚteroRESUMO
A simple and expeditious method for the regioselective synthesis of N1-substituted-4-nitropyrazole-5-carboxylates was developed. The method involves cyclocondensation of ethyl 4-(dimethylamino)-3-nitro-2-oxobut-3-enoate with a series of monosubstituted hydrazines to give N1-substituted-4-nitropyrazole-5-carboxylates with excellent regioselectivity and good yields. Solvent effects on regioselectivity of the cyclocondensation were examined.
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Ácidos Carboxílicos , Hidrazinas , CiclizaçãoRESUMO
BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) has spread worldwide and continues to threaten peoples' health as well as put pressure on the accessibility of medical systems. Early prediction of survival of hospitalized patients will help in the clinical management of COVID-19, but a prediction model that is reliable and valid is still lacking. METHODS: We retrospectively enrolled 628 confirmed cases of COVID-19 using positive RT-PCR tests for SARS-CoV-2 in Tongji Hospital, Wuhan, China. These patients were randomly grouped into a training (60%) and a validation (40%) cohort. In the training cohort, LASSO regression analysis and multivariate Cox regression analysis were utilized to identify prognostic factors for in-hospital survival of patients with COVID-19. A nomogram based on the 3 variables was built for clinical use. AUCs, concordance indexes (C-index), and calibration curves were used to evaluate the efficiency of the nomogram in both training and validation cohorts. RESULTS: Hypertension, higher neutrophil-to-lymphocyte ratio, and increased NT-proBNP values were found to be significantly associated with poorer prognosis in hospitalized patients with COVID-19. The 3 predictors were further used to build a prediction nomogram. The C-indexes of the nomogram in the training and validation cohorts were 0.901 and 0.892, respectively. The AUC in the training cohort was 0.922 for 14-day and 0.919 for 21-day probability of in-hospital survival, while in the validation cohort this was 0.922 and 0.881, respectively. Moreover, the calibration curve for 14- and 21-day survival also showed high coherence between the predicted and actual probability of survival. CONCLUSIONS: We built a predictive model and constructed a nomogram for predicting in-hospital survival of patients with COVID-19. This model has good performance and might be utilized clinically in management of COVID-19.
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COVID-19 , Nomogramas , China/epidemiologia , Humanos , Prognóstico , Estudos Retrospectivos , SARS-CoV-2RESUMO
This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.
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Receptores de Apelina/agonistas , Pirimidinonas/farmacologia , Descoberta de Drogas , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Estrutura Molecular , Pirimidinonas/síntese química , Relação Estrutura-AtividadeRESUMO
AIM: To compare the pregnancy outcomes after day 5 blastocyst-stage embryo transfers (BET) versus day 6 BET following vitrified-warmed cycle and to evaluate whether the number of embryos transferred and the chromosomal status of embryo influence effect estimates. METHODS: A literature search (PubMed, Embase and MEDLINE) up to January 2019 was conducted to identify studies where women with day 6 BET were compared to women with day 5 BET. Only studies published in English language, on peer-reviewed journal were considered eligible. The following subgroup analyses were performed: (i) number of embryos transferred and (ii) chromosomal status of embryo. RESULTS: From a total of 1956 articles identified, 23 observational studies were included in the meta-analysis. We observed that day 6 BET were associated with lower implantation rate (risk ratio, RR: 1.17, 95% confidence interval, CI: 1.10-1.24), clinical pregnancy rate (RR: 1.17, 95% CI: 1.10-1.24), ongoing pregnancy rate (RR: 1.15, 95% CI: 1.07-1.24) and live birth rate (RR: 1.22, 95% CI: 1.11-1.33) than day 5 BET following vitrified-warmed cycle. The subgroup analysis found that the superiority of day 5 BET compared with day 6 BET is influenced by the number of embryos transferred and chromosomal status of embryos. CONCLUSION: Current evidence shows that day 5 BET is superior to day 6 BET following vitrified-warmed cycle in clinical practice. Due to the overall low quality of available evidence, more larger and well-conducted studies are needed to compare the pregnancy outcomes between day 5 and day 6 BET before drawing a clear conclusion.
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Transferência Embrionária/estatística & dados numéricos , Fatores de Tempo , Coeficiente de Natalidade , Técnicas de Cultura Embrionária , Implantação do Embrião , Transferência Embrionária/métodos , Feminino , Humanos , Estudos Observacionais como Assunto , Razão de Chances , Gravidez , Resultado da Gravidez , Taxa de Gravidez , VitrificaçãoRESUMO
Numerous studies concentrate on the association between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphism and male infertility; however, the results remain inconclusive and inconsistent. Hence, this meta-analysis was conducted to get a precise estimation of the correlation. PubMed, Web of Science, Embase, Scopus and China National Knowledge Infrastructure (CNKI) databases were searched to identify the all relevant studies before 3 May 2020. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the strength of the association. Finally, six studies with 1,886 cases and 1,212 controls were included in our study. The result indicated that XRCC1 Arg399Gln polymorphism was significantly associated with male infertility under allelic model (A-allele vs. G-allele: OR = 1.183, p = .003), heterozygote genetic model (AA vs. GA: OR = 1.256, p = .027), recessive genetic model (AA vs. GG + GA: OR = 1.279, p = .012) and dominant genetic model (AA + GA vs. GG: OR = 1.218, p = .026). In addition, in Asian subgroup, statistic correlation remained significant in allelic model (A-allele vs. G-allele: OR = 1.145, p = .025) with rare heterogeneity (I2 = 0%). In summary, our meta-analysis suggested that XRCC1 Arg399Gln polymorphism was significantly associated with male infertility and the A-allele might be a risk factor for this disease, especially in Asians.
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Predisposição Genética para Doença , Infertilidade Masculina , Povo Asiático/genética , Estudos de Casos e Controles , China , Proteínas de Ligação a DNA/genética , Humanos , Infertilidade Masculina/genética , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Raios X , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genéticaRESUMO
PURPOSE: The objective of our meta-analysis was to estimate the effect of VTS on obstetric outcomes of ART singletons. METHODS: PubMed, Embase, MEDLINE, and ClinicalTrials.gov were searched up to January 2019 to find studies reporting the obstetric outcomes of ART singletons with VTS. Dichotomous data were expressed as odds ratios (OR) with 95% confidence intervals (CI). Continuous data were expressed as weighted mean difference (WMD) with 95% CI. RESULTS: A total of 17 observational studies encompassing more than 60,000 ART singletons were included in this meta-analysis. The impact of VTS on singletons was highly dependent on the definition of VTS, precisely, the vanishing timing and intrauterine growth stage. When VTS happened at or before 14 weeks, regardless of intrauterine growth stage, there were no differences in terms of gestational age (GA) [WMD = - 0.08, 95% CI = - 0.27, 0.10], preterm birth (< 37 weeks) (PTB) [OR = 1.23, 95% CI = 0.89, 1.70], and low birth weight (< 2.5 kg) (LBW) [OR = 1.56, 95% CI = 1.00, 2.43] in original singletons versus singleton with VTS. On the contrary, VTS occurred after 14 weeks was associated with significantly shorter GW and lower BW, as well as higher risks of PTB and LBW. When the sac reduced in VTS was an empty gestational sac, there would be no differences in GW, PTB, and LBW between singletons versus singletons with VTS, whereas the loss of a fetus with cardiac-activity was associated with adverse obstetric outcomes. CONCLUSIONS: This meta-analysis suggests whether or not VTS is harmful to obstetric outcomes is highly dependent on the vanishing timing and intrauterine growth stage.
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Aborto Espontâneo/epidemiologia , Gravidez de Gêmeos/genética , Nascimento Prematuro/epidemiologia , Técnicas de Reprodução Assistida/efeitos adversos , Aborto Espontâneo/etiologia , Aborto Espontâneo/patologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido de Baixo Peso/metabolismo , Recém-Nascido de Baixo Peso/fisiologia , Gravidez , Resultado da Gravidez , Nascimento Prematuro/etiologia , Nascimento Prematuro/patologia , Fatores de RiscoRESUMO
BACKGROUND: Non-obstructive azoospermia (NOA) is a multifactorial disorder whose molecular basis remains largely unknown. Circular RNAs (CircRNAs), a novel class of endogenous RNAs, have been recognized to play important roles in many biological processes. However, little is known about the expression patterns and functions of circRNAs in human testes involved in NOA. METHODS: In this study, the testicular circRNA expression profile were explored in NOA patients and the controls by high-throughput circRNA microarray. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to confirm the microarray data. Bioinformatics analyses including the circRNA/miRNA/mRNA interaction network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to predict the functions of differentially expressed circRNAs. RESULTS: A total of 368 differentially down-regulated and 526 up-regulated circRNAs were detected in NOA patients. These findings have been verified by qRT-PCR on 6 selected circRNAs. Among these differentially expressed circRNAs, the hsa_circRNA_0023313 was obviously up-regulated in testicular tissue of NOA patients. The most likely potential target miRNA for hsa_circRNA_0023313 include hsa-miR-520d-3p, hsa-miR-373-3p, hsa-miR-372-3p, hsa-miR-302c-3p and hsa-miR-130b-5p. Function analysis indicated that hsa_circRNA_0023313 was ubiquitin-protein transferase activity and chromatin binding. KEGG analysis revealed that the top five pathways related to hsa_circRNA_0023313 were endocytosis, meiosis, FoxO signaling pathway, ubiquitin mediated proteolysis and AMPK signaling pathway. CONCLUSIONS: This is the first report that the testicular circRNA expression profile is altered in NOA patients indicating circRNAs might play important roles in regulating spermatogenesis and be potential biomarkers for the diagnosis and treatment of NOA.
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Azoospermia/genética , Perfilação da Expressão Gênica/métodos , RNA Circular/genética , Testículo/metabolismo , Adulto , Biologia Computacional/métodos , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Masculino , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genéticaRESUMO
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.
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Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lipase/antagonistas & inibidores , Pirimidinonas/química , Pirimidinonas/farmacologia , Animais , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Humanos , Lipase/sangue , Lipase/metabolismo , Camundongos , Modelos Moleculares , Pirimidinonas/sangue , Pirimidinonas/síntese química , Relação Estrutura-AtividadeRESUMO
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.
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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.
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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.
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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/farmacocinéticaRESUMO
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.
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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 , Redução de Peso/efeitos dos fármacosRESUMO
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.