RESUMO
A series of new quinazolinone-dihydropyrano[3,2-b]pyran derivatives 10A-L were synthesized by simple chemical reactions and were investigated for inhibitory activities against α-glucosidase and α-amylase. New synthesized compounds showed high α-glucosidase inhibition effects in comparison to the standard drug acarbose and were inactive against α-amylase. Among them, the most potent compound was compound 10L (IC50 value = 40.1 ± 0.6 µM) with inhibitory activity around 18.75-fold more than acarboase (IC50 value = 750.0 ± 12.5 µM). This compound was a competitive inhibitor into α-glucosidase. Our obtained experimental results were confirmed by docking studies. Furthermore, the cytotoxicity of the most potent compounds 10L, 10G, and 10N against normal fibroblast cells and in silico druglikeness, ADME, and toxicity prediction of these compounds were also evaluated.
Assuntos
Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , Piranos/química , Piranos/farmacologia , alfa-Glucosidases/metabolismo , Células Cultivadas , Desenho de Fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacocinética , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Piranos/síntese química , Piranos/farmacocinéticaRESUMO
WHAT IS KNOWN AND OBJECTIVE: Acarbose can efficiently block glucose absorption in the intestine as an alpha-glucosidase inhibitor. It is currently manufactured in several oral dosage forms, with the most common types being tablets and chewable tablets. The acarbose tablet (Glucobay® , 50 mg, Bayer) package insert gives instructions for either directly swallowing or chewing then swallowing. This study compared the pharmacodynamic effects of a single formulation of acarbose tablets under these two different administration routes. METHODS: This randomized, crossover study enrolled 24 healthy subjects who were instructed to chew (C group) or swallow (S group) the acarbose tablet. Glucose levels were monitored in subjects for up to 4 h following administration of 75 g of sucrose to establish a baseline firstly, after which subjects in the C and S groups were administered 50- or 100- mg of acarbose along with 75 g of sucrose. Then, subjects entered a 1-week washout period before being crossed over to the alternate dosing route. RESULTS AND DISCUSSION: Compared with the S group, the C group had a lower maximum concentration of serum glucose (Cmax ) and areas under the concentration-time curve (AUC0-2 , AUC0-1.5 ). In addition, the maximum reduction in serum glucose (ΔCmax ) and the reduction in the AUC (AUEC0-1.5 ) were both increased in the S group. This occurred at both the 50 mg and 100 mg dosages. These results indicate that fluctuations in blood glucose were lower following chewing of the acarbose tablet. Both administration routes exhibited similar safety and tolerance profiles. WHAT IS NEW AND CONCLUSION: In summary, chewing acarbose tablets appears to induce a superior glycaemic-controlling effect compared with swallowing them directly, at least with a single dose. It will be important to inform both clinicians and patients about these differences between the two administrations so that informed clinical decisions can be made, as numerous patients with diabetes are inclined to directly swallow acarbose tablets for convenience.
Assuntos
Acarbose/administração & dosagem , Acarbose/farmacologia , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Inibidores de Glicosídeo Hidrolases/farmacologia , Comprimidos/química , Acarbose/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , China , Estudos Cross-Over , Deglutição/fisiologia , Relação Dose-Resposta a Droga , Feminino , Inibidores de Glicosídeo Hidrolases/farmacocinética , Voluntários Saudáveis , Humanos , Masculino , Mastigação/fisiologia , Pessoa de Meia-Idade , Adulto JovemRESUMO
WHAT IS KNOWN AND OBJECTIVE: Acarbose is a poorly absorbed α-glucosidase inhibitor that acts locally in the intestinal tract. Therefore, the evaluation of its bioequivalence (BE) should be based on pharmacodynamic (PD) rather than pharmacokinetic (PK) endpoints. Currently, there is no consensus on the best method for acarbose BE evaluation. The optimal protocol design regarding dosing time/dose and PD parameters requires further exploration. The aim of the study was to identify an optimum protocol for establishing acarbose BE in healthy Chinese volunteers using PD endpoints. METHODS: Three pilot studies were conducted in healthy Chinese subjects. Study 1 was an open, randomized, two-period crossover study using the reference (R) drug at the dose of 1 × 50 mg. Study 1 aimed to determine appropriate dosing time by comparing the PD effect of acarbose between two administration methods. One method was concomitant administration of sucrose and acarbose, and another method was acarbose administration 10 min before sucrose. Study 2 was an open, randomized, three-period crossover study. Subjects were given the R drug at the dose of 1 × 50 mg, 2 × 50 mg or 3 × 50 mg in a random sequence. The aim of Study 2 was to identify a reasonable dose of acarbose in the BE study. Study 3 was conducted with an open, randomized, three-period crossover design using the test (T) or R drug in an R-T-R sequence at the dose of 2 × 50 mg. Study 3 aimed to compare the BE between the R and T drug and determine intra-individual variation. Twelve subjects were recruited in Study 1, Study 2 and Study 3, respectively, with a one-week washout period. Serum glucose and insulin concentrations were determined after sucrose administration (baseline) and sucrose/acarbose co-administration. RESULTS AND DISCUSSION: In Study 1, no significant differences in PD parameters were found between the two administration methods. The results of Study 2 revealed that the optimal dose was between 1 × 50 mg and 2 × 50 mg. The comparison of PD parameters indicated that the rectifying method could distinguish between different formulations. Study 3 showed that the geometric mean ratios of Cmax, r , AUC0-2 h, r and AUC0-4 h, r were 90.06%, 84.55% and 84.21%, respectively, using the rectifying method. The 90% CIs of Cmax, r were within acceptance limits (80.00%-125.00%), whereas that of AUC0-2 h, r and AUC0-4 h, r were out of the range. The intra-individual variation was approximately 21% for R formulation. Based on the variation, the number of subjects needed to identify formulation differences in the pivotal study would be 55 with 90% power at the 5% level of significance. WHAT IS NEW AND CONCLUSION: The results from our study manifested that a randomized, balanced, two-way crossover design was eligible to evaluate acarbose BE. The appropriate dosing time was concomitant administration of sucrose and acarbose, and the optimal dose was 2 × 50 mg. The rectifying method exhibited preferable sensitivity and applicability in acarbose BE evaluation. A practical sample size of the pivotal study would be 55. These results may help to provide new insights into the protocol design of acarbose BE study.
Assuntos
Acarbose/farmacologia , Protocolos Clínicos/normas , Inibidores de Glicosídeo Hidrolases/farmacologia , Acarbose/administração & dosagem , Acarbose/farmacocinética , Adulto , Área Sob a Curva , Glicemia , China , Estudos Cross-Over , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Inibidores de Glicosídeo Hidrolases/farmacocinética , Humanos , Insulina/sangue , Masculino , Taxa de Depuração Metabólica , Sacarose/administração & dosagem , Equivalência Terapêutica , Adulto JovemRESUMO
A series of novel N-alkyl-1-deoxynojirimycin derivatives 25 â¼ 44 were synthesised and evaluated for their in vitro α-glucosidase inhibitory activity to develop α-glucosidase inhibitors with high activity. All twenty compounds exhibited α-glucosidase inhibitory activity with IC50 values ranging from 30.0 ± 0.6 µM to 2000 µM as compared to standard acarbose (IC50 = 822.0 ± 1.5 µM). The most active compound 43 was â¼27-fold more active than acarbose. Kinetic study revealed that compounds 43, 40, and 34 were all competitive inhibitors on α-glucosidase with Ki of 10 µM, 52 µM, and 150 µM, respectively. Molecular docking demonstrated that the high active inhibitors interacted with α-glucosidase by four types of interactions, including hydrogen bonds, π-π stacking interactions, hydrophobic interactions, and electrostatic interaction. Among all the interactions, the π-π stacking interaction and hydrogen bond played a significant role in a various range of activities of the compounds.
Assuntos
Glucosamina/análogos & derivados , Inibidores de Glicosídeo Hidrolases/síntese química , alfa-Glucosidases/metabolismo , 1-Desoxinojirimicina/síntese química , 1-Desoxinojirimicina/farmacocinética , Acarbose/farmacologia , Acarbose/normas , Compostos de Benzilideno/química , Glucosamina/síntese química , Glucosamina/farmacocinética , Inibidores de Glicosídeo Hidrolases/farmacocinética , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
Polysaccharides and fruit extracts are applied in dairy products to enhance their nutritional property, but the effects of such formulations on the functions and biological activities are yet to be explored. Therefore, this study was aimed at evaluating the effect of interactions among milk protein (beta-lactoglobulin; BLG), polysaccharides (pectin, P; chitosan, CH), and anthocyanin (pelargonidin-3-O-glucoside; P3G) in improving the bioavailability and biological activity of P3G. After gastrointestinal digestion (GID), the content of free P3G in different model solutions were as follows: P3G-alone (73.59 µg/mL), P3G-P (66.59 µg/mL), P3G-CH (36.72 µg/mL), P3G-BLG (64.92 µg/mL), P3G-P-BLG (64.92 µg/mL), and P3G-CH-BLG (39.61 µg/mL). Less amount of free P3G in model solutions indicated increased complex formation of P3G with protein and/or polysaccharides during GID. These complexes resulted in protection and progressive release of P3G in the gastrointestinal tract. Chitosan exhibited more protection to P3G compared with P and BLG. In addition, α-glucosidase inhibitory activity and ROS scavenging activities of conjugated-P3G samples were potentially augmented after GID. However, the presence of polysaccharides and protein in the model solutions did not show any negative effect on the biological activity of P3G. Thus, pure P3G can be used as a nutritional ingredient in dairy industries.
Assuntos
Antocianinas/farmacologia , Quitosana/química , Digestão/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/farmacologia , Lactoglobulinas/química , Pectinas/química , Antocianinas/farmacocinética , Antioxidantes , Disponibilidade Biológica , Trato Gastrointestinal/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacocinética , Células Hep G2 , Humanos , alfa-Glucosidases/metabolismoRESUMO
In this study, sandwich-structured magnetic graphene composites with Zn metal-organic framework layer coated on both two sides (denoted as magG@Zn-MOFs) were synthesized. The composites have large specific surface of 114â¯m2â¯gâ»1, uniform porous structure and rapid magnetic separation within 10â¯s. The magG@Zn-MOFs composites were used for extraction of acarbose in plasma prior to its quantitative analysis by LC-MS/MS. The established method has good linearity (10-1000â¯ngâ¯mL-1), satisfactory recovery (94.3-107.5%), low detection limit (as low as 2.5â¯ngâ¯mL-1), good intra-day precision (RSD 3.5-5.3%) and inter-day precision (RSD 6.3-8.1%). Finally, the method was successfully applied to pharmacokinetic study of acarbose in rats.
Assuntos
Acarbose/sangue , Grafite/química , Estruturas Metalorgânicas/química , Zinco/química , Acarbose/farmacocinética , Animais , Cromatografia Líquida , Óxido Ferroso-Férrico/química , Inibidores de Glicosídeo Hidrolases/sangue , Inibidores de Glicosídeo Hidrolases/farmacocinética , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Limite de Detecção , Masculino , Estruturas Metalorgânicas/síntese química , Microesferas , Ratos Sprague-Dawley , Extração em Fase Sólida/métodos , Espectrometria de Massas em TandemRESUMO
1-Phenyl-5-substituted-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole derivatives were synthesized from chalcone derivatives. The structures of compounds were characterized by IR, 1H NMR spectroscopic methods and elemental analysis. All compounds were evaluated for their in vitro antioxidant activity using DPPH and ABTS methods, anti-inflammatory activity using lipoxygenase inhibitory method and antidiabetic activity using the ?-glucosidase inhibitory method. Especially, pyrazoline derivatives exhibited stronger anti-inflammatory activity than the reference drug indomethacin (IC50: 50.45 µM) and their IC50 values were in the range of 0.68 and 4.45 µM. In addition, the ADME properties of all chalcone and pyrazoline derivatives were calculated by Lipinski's and Veber's rules.
Assuntos
Sequestradores de Radicais Livres/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Lipoxigenase/farmacologia , Pirazóis/farmacologia , Chalconas/síntese química , Desenho de Fármacos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacocinética , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacocinética , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacocinética , Pirazóis/síntese química , Pirazóis/farmacocinética , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidoresRESUMO
Many compounds with good inhibitory activity (i.e., high affinity) within in vitro experiments failed in vivo studies due to a lack of efficacy from limited target occupancy (TO) in the drug discovery process. Recently, it was found that rate constants of the formation and dissociation of the binary drug-target complex, rather than affinity, often govern in vivo efficacy. Therefore, the binding kinetics (BK) properties of compound-target interaction are emerging as a pivotal parameter. However, it is obvious that BK rate constants of the compound against target would not be directly linked to the in vivo TO unless the compound concentration in the target vicinity at any time point (TPK) can be evaluated. Here, we developed a novel simulation model to quantitate the dynamic change of target engagement over time in rat with a combined use of BK and TPK features of Epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) on the basis of α-glucosidase (AGH). Analysis of the results displayed that the percent of maximum AGH occupancies by the ECG were varied significantly from 48.9 to 95.3% and by the EGCG slightly from 96 to 99.8%; that the time course of above 70% engagement by ECG spanned a range from 0 to 0.64 h and by EGCG a range of 1.5 to 8.9 h in four different intestinal segments of the rat. It was clearly analyzed how each parameter in the simulation model effected on the in vivo the AGH engagement by ECG and EGCG. Our results provide a novel approach for assessing the potential inhibitory activity of the compounds against AGH.
Assuntos
Inibidores de Glicosídeo Hidrolases/farmacocinética , Saccharomyces cerevisiae/enzimologia , alfa-Glucosidases/metabolismo , Animais , Catequina/análogos & derivados , Catequina/metabolismo , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Absorção Intestinal , Modelos Biológicos , Ratos , Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
BACKGROUND: Postprandial hyperglycemia can be reduced by inhibiting major carbohydrate hydrolyzing enzymes, such as α-glucosidase and α-amylase which is an effective approach in both preventing and treating diabetes. OBJECTIVE: The aim of this study was to synthesize a series of 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl] benzoic acid derivatives and evaluate α-glucosidase and α-amylase inhibitory activity along with molecular docking and in silico ADMET property analysis. METHOD: Chlorosulfonation of 2,4-dichloro benzoic acid followed by reaction with corresponding anilines/amines yielded 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic acid derivatives. For evaluating their antidiabetic potential α-glucosidase and α-amylase inhibitory assays were carried out. In silico molecular docking studies of these compounds were performed with respect to these enzymes and a computational study was also carried out to predict the drug-likeness and ADMET properties of the title compounds. RESULTS: Compound 3c (2,4-dichloro-5-[(2-nitrophenyl)sulfamoyl]benzoic acid) was found to be highly active having 3 fold inhibitory potential against α-amylase and 5 times inhibitory activity against α-glucosidase in comparison to standard drug acarbose. CONCLUSION: Most of the synthesized compounds were highly potent or equipotent to standard drug acarbose for inhibitory potential against α-glucosidase and α-amylase enzyme and hence this may indicate their antidiabetic activity. The docking study revealed that these compounds interact with active site of enzyme through hydrogen bonding and different pi interactions.
Assuntos
Ácido Benzoico/química , Ácido Benzoico/farmacologia , Simulação por Computador , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , Absorção Fisico-Química , Animais , Ácido Benzoico/metabolismo , Células CACO-2 , Cães , Avaliação Pré-Clínica de Medicamentos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacocinética , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Células Madin Darby de Rim Canino , Conformação Proteica , Saccharomyces cerevisiae/enzimologia , alfa-Glucosidases/metabolismoRESUMO
DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives 33d and 35d were selected for preliminary investigations in vivo. X-ray crystal structures help rationalize the observed structure-activity relationships of these novel inhibitors.
Assuntos
Reparo do DNA , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Quinazolinonas/química , Quinazolinonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Domínio Catalítico , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Inibidores de Glicosídeo Hidrolases/farmacocinética , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/metabolismo , Células HeLa , Humanos , Masculino , Camundongos , Modelos Moleculares , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Microencapsulation of polyherbal formulation (PHF) extract was carried out by freeze drying method, by employing gum arabic (GA), gelatin (GE), and maltodextrin (MD) with their designated different combinations as encapsulating wall materials. Antioxidant components (i.e., total phenolic contents (TPC), total flavonoids contents (TFC), and total condensed tannins (TCT)), antioxidant activity (i.e., DPPH, β-carotene & ABTS⺠assays), moisture contents, water activity (aw), solubility, hygroscopicity, glass transition temperature (Tg), particle size, morphology, in vitroα-amylase and α-glucosidase inhibition and bioavailability ratios of the powders were investigated. Amongst all encapsulated products, TB (5% GA & 5% MD) and TC (10% GA) have proven to be the best treatments with respect to the highest preservation of antioxidant components. These treatments also exhibited higher antioxidant potential by DPPH and β-carotene assays and noteworthy for an ABTS⺠assays. Moreover, the aforesaid treatments also demonstrated lower moisture content, aw, particle size and higher solubility, hygroscopicity and glass transition temperature (Tg). All freeze dried samples showed irregular (asymmetrical) microcrystalline structures. Furthermore, TB and TC also illustrated the highest in vitro anti-diabetic potential due to great potency for inhibiting α-amylase and α-glucosidase activities. In the perspective of bioavailability, TA, TB and TC demonstrated the excellent bioavailability ratios (%). Furthermore, the photochemical profiling of ethanolic extract of PHF was also revealed to find out the bioactive compounds.
Assuntos
Antioxidantes/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Preparações de Plantas/farmacologia , Polifenóis/farmacologia , Administração Oral , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Antioxidantes/farmacocinética , Benzotiazóis/química , Disponibilidade Biológica , Compostos de Bifenilo/química , Composição de Medicamentos , Liofilização , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacocinética , Camundongos , Tamanho da Partícula , Picratos/química , Preparações de Plantas/administração & dosagem , Preparações de Plantas/química , Preparações de Plantas/farmacocinética , Polifenóis/administração & dosagem , Polifenóis/química , Polifenóis/farmacocinética , Pós , Solubilidade , Ácidos Sulfônicos/química , Tecnologia Farmacêutica/métodos , Temperatura de Transição , Molhabilidade , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , beta Caroteno/químicaRESUMO
Phytochemical investigation of the oleo-gum resins from Boswellia papyrifera afforded one new triterpene, named 3α-hydroxyurs-5:19-diene (1) together with twelve known compounds including eight triterpenoids (2-9), two diterpenoids (10 and 11) and two straight chain alkanes (12 and 13). Similarly ten more known compounds were isolated from the resin of Boswellia sacra including one triterpene (20) and nine boswellic acids (14-19 and 21-23). Herein the compound 2 was first time reporting from natural source along with complete NMR assignment, while compounds 3-11 are known, but reported for the first time from the resin of B. papyrifera. The structure elucidation was done by advance spectroscopic 1D and 2D NMR techniques viz., 1H, 13C, DEPT, HSQC, HMBC, and COSY, and NEOSY, ESI-MS and compared with the reported literature. All compounds were evaluated for their α-glucosidase inhibitory activity and as result eight of them 1, 3, 10, 11, 15, and 17-19 were found significantly active against α-glucosidase with an IC50 value ranging from 15.0⯱â¯0.84 to 80.3⯱â¯2.33⯵M, while 21 exhibited moderate activity with IC50 of 799.9⯱â¯4.98⯵M. Furthermore, two compounds 24 and 25 were synthesised from 16 and 17 to see the effect of carboxyl group in structural-activity relationship (SAR) study. Compounds 24 and 25 retained good α-glucosidase inhibition as compared to 16 and 17, indicating that carboxylic group play a key role in SAR. In addition, the aforementioned activity of all the active compounds was first time reported for their α-glucosidase inhibition potential. The molecular docking studies showed that all the active compounds well accommodate in the active site of the enzyme. Moreover pharmacokinetic properties of the compounds were predicted in silico, suggesting that the compounds possess drug like properties and excellent ADMET profile.
Assuntos
Boswellia/química , Inibidores de Glicosídeo Hidrolases/química , Resinas Vegetais/química , Triterpenos/química , Domínio Catalítico , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacocinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade , Triterpenos/isolamento & purificação , Triterpenos/farmacocinética , alfa-Glucosidases/químicaRESUMO
Carbohydrate hydrolyzing α-glucosidases are commonly found in microorganisms present in the human intestine microbiome. We have previously reported crystal structures of an α-glucosidase from the human gut bacterium Blaubia (Ruminococcus) obeum (Ro-αG1) and its substrate preference/specificity switch. This novel member of the GH31 family is a structural homolog of human intestinal maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) with a highly conserved active site that is predicted to be common in Ro-αG1 homologs among other species that colonize the human gut. In this report, we present structures of Ro-αG1 in complex with the antidiabetic α-glucosidase inhibitors voglibose, miglitol, and acarbose and supporting binding data. The in vitro binding of these antidiabetic drugs to Ro-αG1 suggests the potential for unintended in vivo crossreaction of the α-glucosidase inhibitors to bacterial α-glucosidases that are present in gut microorganism communities. Moreover, analysis of these drug-bound enzyme structures could benefit further antidiabetic drug development.
Assuntos
Proteínas de Bactérias/metabolismo , Microbioma Gastrointestinal/fisiologia , Inibidores de Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/metabolismo , alfa-Glucosidases/metabolismo , 1-Desoxinojirimicina/análogos & derivados , Proteínas de Bactérias/química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacocinética , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Inositol/análogos & derivados , Modelos Moleculares , Ligação Proteica , Ruminococcus/enzimologia , alfa-Glucosidases/químicaRESUMO
It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-5-(4-( tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5 H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Terpenos/uso terapêutico , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/toxicidade , Estabilidade de Medicamentos , Fígado Gorduroso/tratamento farmacológico , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacocinética , Inibidores de Glicosídeo Hidrolases/toxicidade , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Lactonas/síntese química , Lactonas/farmacocinética , Lactonas/uso terapêutico , Lactonas/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Ratos Sprague-Dawley , Suínos , Terpenos/síntese química , Terpenos/farmacocinética , Terpenos/toxicidade , alfa-Glucosidases/metabolismoAssuntos
Anticolesterolemiantes/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Algoritmos , Anticolesterolemiantes/farmacocinética , Diabetes Mellitus Tipo 2/fisiopatologia , Inibidores de Glicosídeo Hidrolases/farmacocinética , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Humanos , Incretinas/farmacocinética , Incretinas/uso terapêutico , Insulina/farmacocinética , Insulina/uso terapêutico , Resistência à Insulina/fisiologia , Estilo de Vida , Metformina/farmacocinética , Metformina/uso terapêutico , Guias de Prática Clínica como Assunto , Compostos de Sulfonilureia/farmacocinética , Compostos de Sulfonilureia/uso terapêuticoRESUMO
Targeting host functions essential for viral replication has been considered as a broad spectrum and resistance-refractory antiviral approach. However, only a few host functions have, thus far, been validated as broad-spectrum antiviral targets in vivo. ER α-glucosidases I and II have been demonstrated to be essential for the morphogenesis of many enveloped viruses, including members from four families of viruses causing hemorrhagic fever. In vivo antiviral efficacy of various iminosugar-based ER α-glucosidase inhibitors has been reported in animals infected with Dengue, Japanese encephalitis, Ebola, Marburg and influenza viruses. Herein, we established Huh7.5-derived cell lines with ER α-glucosidase I or II knockout using CRISPR/Cas9 and demonstrated that the replication of Dengue, Yellow fever and Zika viruses was reduced by only 1-2 logs in the knockout cell lines. The results clearly indicate that only a partial suppression of viral replication can possibly be achieved with a complete inhibition of ER-α-glucosidases I or II by their inhibitors. We therefore explore to improve the antiviral efficacy of a lead iminosugar IHVR-19029 through combination with another broad-spectrum antiviral agent, favipiravir (T-705). Indeed, combination of IHVR-19029 and T-705 synergistically inhibited the replication of Yellow fever and Ebola viruses in cultured cells. Moreover, in a mouse model of Ebola virus infection, combination of sub-optimal doses of IHVR-19029 and T-705 significantly increased the survival rate of infected animals. We have thus proved the concept of combinational therapeutic strategy for the treatment of viral hemorrhagic fevers with broad spectrum host- and viral- targeting antiviral agents.
Assuntos
Antivirais/farmacologia , Ebolavirus/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/farmacologia , Doença pelo Vírus Ebola/virologia , Animais , Antivirais/farmacocinética , Linhagem Celular , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Inibidores de Glicosídeo Hidrolases/farmacocinética , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/metabolismo , Humanos , Camundongos , Replicação Viral/efeitos dos fármacos , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismoRESUMO
Three new butenolide derivatives, flavipesolides A-C (1-3), along with 13 known compounds (4-13, aspulvinone Q, monochlorosulochrin, and dihydrogeodin), were isolated from the marine-derived Aspergillus flavipes HN4-13 from a Lianyungang coastal sediment sample. The structures were elucidated by spectroscopic evidence. Compounds 4-6 and 9 were noncompetitive α-glucosidase inhibitors with Ki/IC50 values of 0.43/34, 2.1/37, 0.79/19, and 2.8/90 µM, respectively. Compounds 1-3, 8, 10, and 13 are mixed α-glucosidase inhibitors with Ki/IC50 values of (2.5, 19)/44, (3.4, 14)/57, (9.2, 4.7)/95, (6.3, 5.5)/55, (1.4, 0.60)/9.9, and (2.5, 7.2)/33 µM, respectively (IC50 101 µM for acarbose and 79 µM for 1-deoxynojirimycin).
Assuntos
Aspergillus/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/isolamento & purificação , 1-Desoxinojirimicina/farmacologia , 4-Butirolactona/análogos & derivados , Acarbose/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacocinética , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Biologia Marinha , Estrutura Molecular , alfa-Glucosidases/metabolismoRESUMO
The aim of this study was to examine the effects of food thickeners on the pharmacodynamics of voglibose, an α-glucosidase inhibitor. The pharmacodynamics of voglibose were examined in an open-label study in 9 healthy participants after the ingestion of a single oral dose of a voglibose oral-disintegrating tablet, with and without food thickener immersion. The area under the incremental blood sugar concentration-time curve was larger and the rate of increments in the blood sugar concentration was higher with the voglibose oral-disintegrating tablets immersed in the food thickener than with the tablets that were not immersed. Immersing the voglibose oral-disintegrating tablets in the food thickener possibly delayed their disintegration rate. This suggests that commercially available food thickeners may be associated with changes in the disintegration of voglibose oral-disintegrating tablets and should therefore be used carefully in certain clinical situations.
Assuntos
Glicemia/metabolismo , Aditivos Alimentares/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacocinética , Hipoglicemiantes/farmacocinética , Inositol/análogos & derivados , Período Pós-Prandial , Administração Oral , Adulto , Fenômenos Químicos , Feminino , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Inositol/administração & dosagem , Inositol/farmacocinética , Inositol/farmacologia , Masculino , Pessoa de Meia-Idade , Solubilidade , ComprimidosRESUMO
The bioactive flavonoid fisetin (FS) is a diet-derived antioxidant that is being increasingly investigated for its health-promoting effects. Unfortunately, the poor physicochemical and pharmacokinetic properties affect and limit the clinical application. In this study, novel polymeric nanoparticles (NPs), based on Poly-(ε-caprolactone) (PCL) and PLGA-PEG-COOH, encapsulating FS were formulated as suitable oral controlled release systems. Results showed NPs having a mean diameter of 140-200nm, and a percent loading of FS ranging from 70 to 82%. In vitro release studies revealed that NPs are able to protect and preserve the release of FS in gastric simulated conditions, also controlling the release in the intestinal medium. Moreover, the DPPH and ABTS scavenging capacity of FS, as well as α-glucosidase inhibition activity, that resulted about 20-fold higher than commercial Acarbose, were retained during nanoencapsulation process. In summary, our developed NPs can be proposed as an attractive delivery system to control the release of antioxidant and anti-hyperglycemic FS for nutraceutical and/or therapeutic application.
Assuntos
Antioxidantes , Suplementos Nutricionais , Flavonoides , Inibidores de Glicosídeo Hidrolases , Nanocápsulas/química , Antioxidantes/química , Antioxidantes/farmacocinética , Flavonoides/química , Flavonoides/farmacocinética , Flavonóis , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacocinética , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismoRESUMO
OBJECTIVES: Renal function may progressively decline in patients with Fabry disease. This study assessed pharmacokinetics, safety, and tolerability of a single oral dose of migalastat HCl 150 mg in subjects with normal or mildly, moderately, or severely impaired renal function. METHODS: Volunteers were enrolled into two cohorts stratified for renal function calculated using the Cockcroft-Gault equation for creatinine clearance. Pharmacokinetic parameters determined were: area under the concentration-time curve (AUC) from time zero to the last measurable concentration postdose (AUC0-t ) and extrapolated to infinity (AUC0-∞ ), maximum observed concentration (Cmax ), time to Cmax (tmax ), concentration at 48 hours postdose (C48h ), terminal elimination half-life (t1/2 ), oral clearance (CL/F), and apparent terminal elimination rate constant (λz) (ClinicalTrials.gov registration: NCT01730469). RESULTS: Thirty-two subjects enrolled and completed the study (Cohort 1: n = 24; Cohort 2: n = 8). Migalastat clearance decreased with increasing renal impairment, resulting in increases in migalastat HCl plasma t1/2 , AUC0-∞ , and C48h compared with subjects with normal renal function. Incidence of adverse events was comparable across all renal function groups. CONCLUSIONS: Plasma migalastat clearance decreased as degree of renal impairment increased. Data from the migalastat HCl clinical program will guide dosing and intervals for patients with Fabry disease with renal impairment.