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1.
Eur J Pharm Biopharm ; 144: 79-90, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499162

RESUMO

Despite the fact that solid dispersions are gaining momentum, the number of polymers that have been used as a carrier during the past 50 years is rather limited. Recently, the poly(2-alkyl-2-oxazoline) (PAOx) polymer class profiled itself as a versatile platform for a wide variety of applications in drug delivery, including their use as amorphous solid dispersion (ASD) carrier. The aim of this study was to investigate the potential of poly(2-ethyl-2-oxazoline) (PEtOx) by applying a benchmark approach with well-known, commercially available carriers (i.e. polyvinylpyrrolidone (PVP) K30, poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) 64 and hydroxypropylmethylcellulose (HPMC)). For this purpose, itraconazole (ITC) and fenofibrate (FFB) were selected as poorly water-soluble model drugs. The four polymers were compared by establishing their supersaturation maintaining potential and by investigating their capability as carrier for ASDs with high drug loadings. Spray drying, as well as hot melt extrusion and cryo-milling were implemented as ASD manufacturing technologies for comparative evaluation. For each manufacturing technique, the formulations with the highest possible drug loadings were tested with respect to in vitro drug release kinetics. This study indicates that PEtOx is able to maintain supersaturation of the drugs to a similar extent as the commercially available polymers and that ASDs with comparable drug loadings can be manufactured. The results of the in vitro dissolution tests reveal that high drug release can be obtained for PEtOx formulations. Overall, proof-of-concept is provided for the potential of PEtOx for drug formulation purposes.


Assuntos
Portadores de Fármacos/química , Poliaminas/química , Solubilidade/efeitos dos fármacos , Química Farmacêutica/métodos , Cristalização/métodos , Dessecação/métodos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Derivados da Hipromelose/química , Polímeros/química , Povidona/química , Pirrolidinas/química , Compostos de Vinila/química
2.
Phys Chem Chem Phys ; 21(32): 17950-17958, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31384849

RESUMO

The A. aeolicus intrinsically disordered protein FlgM has four well-defined α-helices when bound to σ28, but in water FlgM undergoes a change in tertiary structure. In this work, we investigate the structure of FlgM in aqueous solutions of the ionic liquid [C4mpy][Tf2N]. We find that FlgM is induced to fold by the addition of the ionic liquid, achieving average α-helicity values similar to the bound state. Analysis of secondary structure reveals significant similarity with the bound state, but the tertiary structure is found to be more compact. Interestingly, the ionic liquid is not homogeneously dispersed in the water, but instead aggregates near the protein. Separate simulations of aqueous ionic liquid do not show ion clustering, which suggests that FlgM stabilizes ionic liquid aggregation.


Assuntos
Proteínas de Bactérias/química , Imidas/química , Proteínas Intrinsicamente Desordenadas/química , Líquidos Iônicos/química , Modelos Moleculares , Pirrolidinas/química , Bases de Dados de Proteínas , Conformação Proteica em alfa-Hélice , Dobramento de Proteína , Termodinâmica , Água
3.
Eur J Pharm Biopharm ; 143: 8-17, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31398439

RESUMO

In this paper, we employed Broadband Dielectric Spectroscopy (BDS) in order to determine the effect of the high pressure on the solubility limits of the amorphous flutamide within Kollidon VA64 matrix. In order to achieve this goal, drug-polymer systems have been examined: (i) at ambient pressure and both isothermal and nonisothermal conditions by means of BDS as well as Differential Scanning Calorimetry (DSC), to validate proposed method; (ii) at high pressure conditions (20 and 50 MPa) and elevated temperatures (343 K, 353 K and 363 K) by means of dielectric spectroscopy. Our studies revealed that regardless of applied pressure the solubility of the flutamide within the co-polymer matrix increases with increasing temperature at isobar conditions. Moreover, our results clearly indicate that with increasing pressure the solubility of the drug within the polymer matrix is decreasing at isothermal conditions. Therefore, during the solubility limit studies one should consider the situation in which by increasing the pressure (at constant temperature) would achieve an effect similar to the lowering of the temperature (at constant pressure).


Assuntos
Flutamida/química , Polímeros/química , Varredura Diferencial de Calorimetria/métodos , Espectroscopia Dielétrica/métodos , Pressão , Pirrolidinas/química , Solubilidade , Temperatura Ambiente , Compostos de Vinila/química
4.
Chem Biol Interact ; 309: 108682, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31163137

RESUMO

Casualties caused by nerve agents, potent acetylcholinesterase inhibitors, have attracted attention from media recently. Poisoning with these chemicals may be fatal if not correctly addressed. Therefore, research on novel antidotes is clearly warranted. Pyridinium oximes are the only clinically available compounds, but poor penetration into the blood-brain barrier hampers efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in SAR studies, we synthesized and evaluated neutral aryloximes as reactivators for acetylcholinesterase inhibited by NEMP, a VX surrogate. Although few tested compounds reached comparable reactivation results with clinical standards, they may be considered as leads for further optimization.


Assuntos
Acetilcolinesterase/metabolismo , Reativadores da Colinesterase/síntese química , Oximas/química , Pirrolidinas/química , Acetilcolinesterase/química , Animais , Antídotos/síntese química , Antídotos/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Reativadores da Colinesterase/metabolismo , Enguias , Compostos Organotiofosforados/química , Compostos Organotiofosforados/metabolismo , Oximas/metabolismo , Pirrolidinas/metabolismo , Relação Estrutura-Atividade
5.
Chem Pharm Bull (Tokyo) ; 67(6): 599-603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155566

RESUMO

The PF-543 is known as a potent and selective inhibitor of sphingosine kinase (SK) 1 amongst all the SK inhibitors known to date. In a recently reported study by Pfizer on the synthesis of PF-543 derivatives and the SK inhibitory effects, the introduction of propyl moiety into sulfonyl group of PF-543 in the case of 26b revealed an excellent result of 1.7 nM of IC50 of SK1, suggesting the potential substitution of chain structure for benzenesulfonyl structure. In the present work, we aimed for identification of antitumor activity and inhibitory effects of PF-543 derivative containing aliphatic long chain (similar to known SK inhibitors) on SK1. The synthesized compound 2 exhibited an inhibitory effect on SK1 in a manner similar to that of PF-543; the PF-543 derivative manifested similar antitumor activity on HT29, HCT116 (colorectal cancer cell line), and AGS (gastric cancer cell line) cells. Also, from the docking study conducted with PF-543 and compound 2, it was apparent that the aliphatic chain in compound 2 could probably replace benzenesulfonyl structure of PF-543.


Assuntos
Antineoplásicos/síntese química , Pirrolidinas/química , Sulfonas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia
6.
J Chromatogr Sci ; 57(7): 600-605, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095671

RESUMO

A simple and sensitive bioanalytical HPLC-UV method has been developed and validated for quantification of eliglustat in rat plasma. The liquid-liquid extraction method was found to be more efficient compared to protein precipitation technique. Chromatographic separation of eliglustat was achieved using Kromasil C18 column with a mobile phase consisting of a mixture of methanol and ammonium acetate (pH 3.2) in a ratio of 60:40. Detection wavelength was set at 282 nm. The developed method was specific, accurate, precise with good recovery and stability profile. The calibration curve constructed over a range of 0.3-10 µg/mL was linear (R2 > 0.997). Accuracy in intra and inter-day assay were found to be 96.27-107.35% and 96.80-106.57%, respectively. The corresponding precision (%CV) values were within 4.31-10.90% and 4.82-9.97%, respectively. Till date, no method is available for bioanalysis of eliglustat in any type of biological matrix. This is the first time to report a bioanalytical method for this molecule. The developed bioanalytical method was applied to quantitate eliglustat in the plasma samples of a single dose oral pharmacokinetic study in Sprague Dawley rat.


Assuntos
Pirrolidinas/sangue , Animais , Cromatografia Líquida de Alta Pressão/métodos , Limite de Detecção , Modelos Lineares , Masculino , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
7.
Eur J Pharm Biopharm ; 141: 149-160, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132400

RESUMO

The aim of this work was to investigate the relationship between formulation material properties, process parameters and process performance for the manufacturing of amorphous solid dispersions via hot-melt extrusion (HME) using experimentation coupled with process modeling. Specifically, we evaluated the impact of the matrix copovidone melt rheology with and without the addition of a plasticizing surfactant, polysorbate 80, while also varying the process parameters, barrel temperature and screw speed, and keeping fill volume constant. To correlate the process performance to a critical quality attribute, we used telmisartan as an indicator substance by processing at temperatures below its solubility temperature in the polymeric matrix. We observed a broader design space of HME processes for the plasticized formulation with respect to screw speed than for the copovidone-only matrix formulation. This observation was determined by the range of observed melt temperatures in the extruder, both measured and simulated. The reason was not primarily linked to a reduced shear-thinning behavior, characterized by the power law index, n, but instead more to an overall reduced melt viscosity during extrusion and zero-shear rate viscosity, η0, accordingly. We also found that the amount of residual crystallinity of telmisartan correlated with the simulated maximum melt temperature in the extruder barrel. This finding confirmed the applicability of the temperature-dependent API-matrix solubility phase diagram for HME to process development. Given the complex inter-dependent relationships between material properties, process and performance, process modeling combined with reduced laboratory experimentation was established as a holistic approach for the evaluation of Quality-by-Design-based HME process design spaces.


Assuntos
Polímeros/química , Povidona/química , Telmisartan/química , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Temperatura Alta , Ciência dos Materiais/métodos , Polissorbatos/química , Pirrolidinas/química , Reologia , Solubilidade/efeitos dos fármacos , Compostos de Vinila/química , Viscosidade/efeitos dos fármacos
8.
Eur J Pharm Biopharm ; 141: 111-120, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100430

RESUMO

The number of models for assessing the solubility of active pharmaceutical ingredients (APIs) in polymeric matrices on the one hand and the extent of available associated data on the other hand has been rising steadily in the past few years. However, according to our knowledge an overview on the methods used for prediction and the respective experimental data is missing. Therefore, we compiled experimental data, the techniques used for their determination and the models used for estimating the solubility. Our focus was on polymers commonly used in spray drying and hot-melt extrusion to form amorphous solid dispersions (ASDs), namely polyvinylpyrrolidone grades (PVP), polyvinyl acetate (PVAc), vinylpyrrolidone-vinyl acetate copolymer (copovidone, COP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft polymer (Soluplus®, SOL), different types of methacrylate copolymers (PMMA), polyethylene glycol grades (PEG) and hydroxypropyl-methylcellulose grades (HPMC). The literature data were further supplemented by our own results. The final data set included 37 APIs and two sugar derivatives. The majority of the prediction models was constituted by the melting point depression method, dissolution endpoint measurements, indirect solubility determination by Tg and the use of low molecular weight analogues. We observed that the API solubility depended more on the working group which conducted the experiments than on the measuring technique used. Furthermore, this compilation should assist researchers in choosing a prediction method suited for their investigations. Furthermore, a statistical assessment using recursive feature elimination was performed to identify descriptors of molecules, which are connected to the API solubility in polymeric matrices. It is capable of predicting the criterium 20% API soluble at 100 °C (Yes/No) for an unknown compound with a balanced accuracy of 71%. The identified 8 descriptors to be connected to API solubility in polymeric matrices were the number of hydrogen bonding donors, three descriptors related to the hydrophobicity of the molecule, glass transition temperature, fractional negative polar van der Waals surface area, out-of-plane potential energy and the fraction of rotatable bonds. Finally, in addition to our own model, the data set should help researchers in training their own solubility prediction models.


Assuntos
Preparações Farmacêuticas/química , Polímeros/química , Solubilidade/efeitos dos fármacos , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Derivados da Hipromelose/química , Polietilenoglicóis/química , Polivinil/química , Povidona/análogos & derivados , Povidona/química , Pirrolidinas/química , Temperatura de Transição , Compostos de Vinila/química
9.
Chem Commun (Camb) ; 55(35): 5171-5174, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30984932

RESUMO

The organocatalytic enantioselective Friedel-Crafts alkylation of phloroglucinol derivatives with enals is reported, providing general access to the benzylic chiral centers shown in a variety of phloroglucinol natural products. The synthetic utility is demonstrated by the very concise asymmetric total synthesis of aflatoxins B2.


Assuntos
Aflatoxinas/síntese química , Floroglucinol/análogos & derivados , Aldeídos/química , Alcenos/química , Alquilação , Catálise , Pirrolidinas/química , Estereoisomerismo
10.
Eur J Pharm Sci ; 133: 79-85, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30890364

RESUMO

The aim of this study was to evaluate the potential of combining multiple ASDs based on water soluble and insoluble polymers to reach and maintain poorly soluble posaconazole (PCZ) supersaturation over time. ASDs of PCZ were obtained with PVP/VA64 or an ammonio methacrylate copolymer by solvent evaporation method with a fixed 20% (wt/wt%) drug loading ratio and physical mixtures of these ASDs were prepared at various proportions. ASDs were characterized by Fourier transform infrared spectroscopy (FT-IR) and powder X-ray diffraction (PXRD) and compared to their respective physical mixture with crystalline PCZ. Crystalline PCZ equilibrium solubility was determined at pH 1.2-2 range. Dissolution profiles were constructed under non-sink condition with an adapted dissolution system. PXRD analysis demonstrated that both ASDs were at the amorphous state and FT-IR spectroscopy revealed that the analytical signal of PCZ was also absent in both ASDs. Equilibrium solubility of crystalline PCZ varied between 26.36 ±â€¯0.32 (pH 2) to 609.33 ±â€¯3.68 (pH 1.2) µg/mL. All ASDs reached higher concentrations than the equilibrium solubility of crystalline PCZ during dissolution. PVP/VA64 ASDs showed dominance over PCZ dissolution and recrystallization rates whereas Eudragit RS PO ASD alone did not cause PCZ recrystallization whatsoever. The combination containing 20 mg PVP/VA64 + 80 mg Eudragit RS PO as PCZ carriers obtained the highest AUC, suggesting that even after the PVP/VA64 part was completely dissolved, reaching a concentration above crystalline PC Cs, the insoluble polymer could still release PCZ slowly and maintain supersaturation over time. The research demonstrated a potential of combining multiple ASDs to achieve distinct dissolution profiles while increasing the kinetic solubility of poorly soluble drugs.


Assuntos
Antifúngicos/química , Excipientes/química , Ácidos Polimetacrílicos/química , Pirrolidinas/química , Triazóis/química , Compostos de Vinila/química , Cristalização , Formas de Dosagem , Liberação Controlada de Fármacos , Cinética , Solubilidade
11.
Biol Pharm Bull ; 42(3): 401-410, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828072

RESUMO

Ridaifen (RID)-B is an analog derived from tamoxifen (TAM). TAM has an antitumor effect by acting as an antagonist to estrogen receptor (ER). However, TAM is known to also induces apoptosis in cancer cells that do not have ER. We clarified that RID-B induces cell death at a lower concentration than TAM, and causes ER-independent apoptosis and autophagy. Based on the results of previous studies, we assumed that RID-B had a unique target different from ER and examined structural activity correlation to determine what kinds of structural features are related to RID-B activity. As a result, we found there was activity even without one of phenyl groups (Ar3) in RID-B and revealed that two pyrrolidine side chains peculiar to RID-B are related to the action. Furthermore, analogs with shorter alkyl side chains induced autophagy, but analogs with certain length of alkyl side chains induced apoptosis. Also, although there is no doubt that RID-B induces apoptosis by causing mitochondrial injury, our results suggested that such injury induced mitochondria-selective autophagy. We revealed that RID-B induce mitophagy and that this mitophagy is a defense mechanism against RID-B. Our results suggest that autophagy was induced against apoptosis caused by mitochondrial dysfunction in RID-B, so the combination of autophagy inhibitor and anticancer-drug can be effective for cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pirrolidinas/química , Pirrolidinas/farmacologia , Tamoxifeno/análogos & derivados , Actinas/genética , Actinas/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Degradação Mitocondrial , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tamoxifeno/química , Tamoxifeno/farmacologia
12.
Food Chem ; 287: 265-272, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30857698

RESUMO

In this study, the degradation of tropane alkaloids in pasta under boiling (100 °C during 10 min) and tea making (100 °C and let cool 5 min) conditions has been evaluated for the first time. Pasta and green tea were contaminated with Datura Stramonium and Brugmansia Arborea seeds (pasta and green tea), whereas coca leaf tea was directly analysed. The compounds were extracted using solid-liquid extraction coupled to a preconcentration stage (only for the cooking water), and the compounds were analysed by liquid chromatography coupled to mass spectrometry (Exactive-Orbitrap analyser). Degradation studies indicate that concentration of tropane alkaloids decreases, and it depends on the compound, observing the highest degradation for tropinone, tropane, cuscohygrine and tropine, as well as it was observed that compounds migrated to the aqueous phase during cooking step. Finally, post-targeted analysis was performed and other tropane alkaloids were found, as scopine, tigloidine or convolvine, showing a similar behaviour under cooking conditions.


Assuntos
Coca , Contaminação de Alimentos , Solanaceae , Chá/química , Tropanos/química , Acetona/análogos & derivados , Acetona/química , Cromatografia Líquida , Datura stramonium , Fagopyrum , Espectrometria de Massas , Folhas de Planta , Pirrolidinas/química , Sementes , Extração em Fase Sólida , Temperatura de Transição
13.
Molecules ; 24(5)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30832206

RESUMO

In this study, we report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of the adenosine triphosphate (ATP) binding site driven by structure-based drug design. For an upscale compatible multigram synthesis of the functionalized pyrrolidine scaffolds, we used a chiral pool synthetic route starting from methionine. Biological evaluation of key compounds in kinase and cellular assays revealed significant effects of the scaffolds towards activity and selectivity, however, the absolute configuration of the chiral moieties only exhibited a limited effect on inhibitory activity. X-ray crystallographic analysis of ligand-CK1δ complexes confirmed the expected binding mode of the 3,4-diaryl-isoxazole inhibitors. Surprisingly, the original compounds underwent spontaneous Pictet-Spengler cyclization with traces of formaldehyde during the co-crystallization process to form highly potent new ligands. Our data suggests chiral "ribose-like" pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds.


Assuntos
Caseína Quinase Idelta/antagonistas & inibidores , Desenho de Drogas , Inibidores Enzimáticos/química , Isoxazóis/química , Trifosfato de Adenosina/química , Sítios de Ligação , Caseína Quinase Idelta/química , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Ligantes , Complexos Multiproteicos/química , Pirrolidinas/química , Relação Estrutura-Atividade
14.
Pharmacol Rep ; 71(2): 357-360, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30844686

RESUMO

BACKGROUND: A variety of spirooxindoles have demonstrated cytotoxic activity toward several cancer cell lines. This study investigates the cytotoxicity of five novel spirooxindole-pyrrolidines by using the Vero and HeLa cell lines. METHODS: Vero and HeLa cells were treated with the synthesized spirooxindoles, and the cytotoxicity was evaluated by using the AlamarBlue Cell Viability Reagent and live/dead assay. RESULTS: A series of poly-substituted pyrrolidines differing in nature and in substituent positions were obtained, with yields of 42-63%. Of the synthesized cycloadducts, 3-picolinoyl-4-(2,4-dichlorophenyl)-5-phenylspiro[indoline-3,2'-pyrrolidine]-2'-one (4) was the most cytotoxic (IC50 < 20 µg/ml for both cell lines). Besides, 3-picolinoyl-4-(2-chlorophenyl)-5-phenylspiro[indoline-3,2'-pyrrolidine]-2'-one (1) was three times more toxic to the HeLa cancer cell line (IC50 = 70 µg/ml) than it was to the Vero healthy cell line. The cytotoxicity of compounds 1 and 4 was confirmed with a live/dead assay. The cytotoxicity of a molecule was found to depend on the substitution nature on the benzene ring at the C-4 atom. CONCLUSION: 3-Picolinoyl-4-(2-chlorophenyl)-5-phenylspiro[indoline-3,2'-pyrrolidine]-2'-one (1) can be used as a source for the synthesis of novel therapeutic agents against cancer.


Assuntos
Antineoplásicos/farmacologia , Oxindois/farmacologia , Pirrolidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Cercopithecus aethiops , Células HeLa , Humanos , Concentração Inibidora 50 , Oxindois/síntese química , Oxindois/química , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-Atividade , Células Vero
15.
Curr Drug Metab ; 20(4): 254-265, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30727881

RESUMO

BACKGROUND: As part of an integrated and innovative approach to accelerate the clinical development of the dual receptor antagonist ACT-541468, 6 healthy subjects in one cohort in a first-in-humans (FIH) study received an oral dose of 50 mg non-labeled ACT-541468 together with a microtracer amount of 250 nCi of 14C-labeled ACT- 541468 to investigate its absorption, distribution, metabolism, and excretion (ADME). METHODS: Using accelerator mass spectrometry (AMS), radiochromatograms were constructed for fractionated plasma, urine, and feces samples. Subsequently, the structures of the metabolites were elucidated using high performance liquid chromatography (HPLC) coupled with high resolution mass spectrometry. RESULTS: In total 77 metabolites have been identified of which 30, 28, and 60 were present in plasma, urine, and feces, respectively. In plasma, the major metabolites were the mono-oxidized benzylic alcohol M3, the ACT-541468 aldehyde M1, formed by further oxidation of M3 in the benzylic position, and the doubly oxidized M10, formed by (1) benzylic oxidation of M3 (loss of one molecule of water and one molecule of ammonia) and (2) additional loss of water from the oxidized pyrrolidine ring of M5. Transformation of the pyrrolidine to a 6-membered ring was detected. Metabolites that accounted for more than 5% of total radioactivity in excreta were M2, which is also formed by oxidation at the benzylic position, M4, formed by demethylation of the methoxy-group, M7 and A6, both formed by oxidation of M4, and M10, the only major metabolite detected in urine. CONCLUSION: In conclusion, ACT-541468 is extensively metabolized predominantly by oxidative transformations.


Assuntos
Imidazóis/farmacocinética , Antagonistas dos Receptores de Orexina/farmacocinética , Pirrolidinas/farmacocinética , Área Sob a Curva , Radioisótopos de Carbono , Relação Dose-Resposta a Droga , Método Duplo-Cego , Meia-Vida , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Imidazóis/metabolismo , Estrutura Molecular , Antagonistas dos Receptores de Orexina/administração & dosagem , Antagonistas dos Receptores de Orexina/química , Antagonistas dos Receptores de Orexina/metabolismo , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Pirrolidinas/metabolismo
16.
Org Lett ; 21(5): 1287-1291, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30735051

RESUMO

The burnettramic acids are a new class of antibiotics from an Australian fungus Aspergillus burnettii. The rare bolaamphiphilic scaffold consists of ß-d-mannose linked to a pyrrolizidinedione unit via a 26-carbon chain. The most abundant metabolite displayed potent in vitro antifungal activity. Comparative genomics identified the hybrid PKS-NRPS bua gene cluster, which was verified by heterologous pathway reconstitution in Aspergillus nidulans.


Assuntos
Antibacterianos/síntese química , Aspergillus/química , Compostos Heterocíclicos com 2 Anéis/química , Antibacterianos/biossíntese , Aspergillus/metabolismo , Austrália , Isomerismo , Manose/química , Estrutura Molecular , Família Multigênica , Oxirredução , Pirrolidinas/química , Metabolismo Secundário
17.
Eur J Med Chem ; 167: 269-290, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776691

RESUMO

ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50 µM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 µM, 1.56 µM, 0.78 µM and 0.72 µM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 µM on both strains, and MIC value of 32 µM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.


Assuntos
Antibacterianos/química , DNA Topoisomerase IV/antagonistas & inibidores , Pirrolidinas/química , Inibidores da Topoisomerase II/farmacologia , Amidas/química , Antibacterianos/farmacologia , DNA Girase/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Inibidores da Topoisomerase II/química
18.
Biochimie ; 160: 24-27, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30763638

RESUMO

A Mg2+-water bridge between the C-3, C-4 diketo moiety of fluoroquinolones and the conserved amino acid residues in the GyrA/ParC subunit is critical for the binding of a fluoroquinolone to a topoisomerase-DNA covalent complex. The fluoroquinolone UING-5-249 (249) can bind to the GyrB subunit through its C7-aminomethylpyrrolidine group. This interaction is responsible for enhanced activities of 249 against the wild type and quinolone-resistant mutant topoisomerases. To further evaluate the effects of the 249-GyrB interaction on fluoroquinolone activity, we examined the activities of decarboxy- and thio-249 against DNA gyrase and conducted docking studies using the structure of a gyrase-ciprofloxacin-DNA ternary complex. We found that the 249-GyrB interaction rescued the activity of thio-249 but not that of decarboxy-249. A C7-group that binds more strongly to the GyrB subunit may allow for modifications at the C-4 position, leading to a novel compound that is active against the wild type and quinolone-resistant pathogens.


Assuntos
Ciprofloxacino/metabolismo , DNA Girase/metabolismo , DNA Bacteriano/metabolismo , Fluoroquinolonas/metabolismo , Pirrolidinas/química , Staphylococcus aureus/enzimologia , Compostos de Sulfidrila/química , Antibacterianos/química , Antibacterianos/metabolismo , Ciprofloxacino/química , DNA Girase/química , DNA Girase/genética , DNA Bacteriano/química , DNA Bacteriano/genética , Descarboxilação , Escherichia coli/metabolismo , Fluoroquinolonas/química , Testes de Sensibilidade Microbiana , Subunidades Proteicas
19.
Molecules ; 24(2)2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30669468

RESUMO

A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal ß-glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.


Assuntos
Ceramidas/química , Inibidores Enzimáticos/química , Glucosilceramidase/antagonistas & inibidores , Imino Açúcares/química , Animais , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Glucosilceramidase/metabolismo , Humanos , Hidrólise , Imino Piranoses/química , Isomerismo , Lisossomos , Melanoma Experimental , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/química , Ligação Proteica , Pirrolidinas/química , Relação Estrutura-Atividade
20.
Drug Metab Dispos ; 47(3): 238-248, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30530814

RESUMO

Nitrile group biotransformation is an unusual or minor metabolic pathway for most nitrile-containing drugs. However, for some cyanopyrrolidine dipeptidyl peptidase 4 (DPP-4) inhibitors (vildagliptin, anagliptin, and besigliptin, but not saxagliptin), the conversion of nitrile group into carboxylic acid is their major metabolic pathway in vivo. DPP-4 was reported to be partly involved in the metabolism. In our pilot study, it was also observed that saxagliptin, a DPP-4 specific inhibitor, decreased the plasma exposures of besigliptin carboxylic acid in rats by only 20%. Therefore, it is speculated that some other enzymes may participate in nitrile group hydrolysis. After incubating gliptins with the cytosol, microsomes, and mitochondria of liver and kidney, carboxylic acid metabolites could all be formed. In recombinant DPP family such as DPP-4, DPP-2, DPP-8, DPP-9, and fibroblast activation protein-α, more hydrolytic metabolites were found. Among them, DPP-2 had the highest hydrolytic capacity besides DPP-4, and the DPP-4 inhibitor saxagliptin and DPP-2 inhibitor AX8819 can both inhibit the hydrolysis of gliptins. Western blot results showed that DPP-2 and DPP-4 existed in the aforementioned subcellular organelles at varying amounts. In rats, AX8819 decreased the plasma exposures of besigliptin carboxylic acid by 40%. The amide intermediates of gliptins were detected in vivo and in vitro. When the amide derivatives of gliptins were incubated with DPP-4, they were completely hydrolyzed at a rate far more than that from the parent drug, including saxagliptin-amide. Therefore, it was proposed that gliptins, except saxagliptin, were initially hydrolyzed to their amides by DPPs, which was the rate-limiting step in generating the carboxylic end product.


Assuntos
Inibidores da Dipeptidil Peptidase IV/metabolismo , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Pirrolidinas/metabolismo , Administração Oral , Animais , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/química , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Humanos , Hidrólise , Masculino , Microssomos Hepáticos , Nitrilos/metabolismo , Projetos Piloto , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo
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