Synthesis and Evaluation of Dapagliflozin Ester Prodrugs with Improved Hygroscopicity and Thermal Stability

2020 ◽  
Vol 17 (11) ◽  
pp. 1409-1421
Author(s):  
Si Young Sung ◽  
Yu Na Chae ◽  
Dae Young Lee ◽  
Kyeong Min Kim ◽  
Eun Jung Kim ◽  
...  
Keyword(s):  
Thermal Stability ◽  
Physical Property ◽  
Parent Drug ◽  
The Body ◽  
The Novel ◽  
Pharmaceutical Production ◽  
Extreme Care ◽  
In Vitro Stability ◽  
Ester Prodrugs

Background: Dapagliflozin, developed as an SGLT-2 inhibitor, has a low melting point and high hygroscopicity, which needs extreme care during pharmaceutical production to keep the active pharmacological property. Various attempts have been made to overcome these problematic properties. Objectives: To develop dapagliflozin prodrugs that have similar pharmacological effects with improved hygroscopicity and thermal stability. Methods: The novel dapagliflozin ester prodrugs containing pharmaceutically acceptable moieties were synthesized and their pharmacokinetics (PK) and physical properties were compared with dapagliflozin propanediol hydrate (DPD, Farxiga®). The PK in dog and rat, in vitro stability, hygroscopicity, and physical property studies in accelerated conditions (40°C, 75% RH) were performed with prodrugs. Results and Discussion: Among the eight synthesized prodrugs, Cmax and AUC0-48h values of prodrug 8b (1.35 μg/ml and 14.78 μg·h/ml, respectively) were similar to those of DPD (1.67 μg/ml and 14.27 μg·h/ml, respectively). However, the rest of the prodrugs 8a, 8c, 8d, 8e, 8f, 8g and 8h showed significantly lower Cmax and AUC0-48h values than DPD. Prodrug 8b completely converted into parent drug in the body. Conclusion: The novel prodrug 8b exhibited comparative PK profile to that of DPD, but with low hygroscopic property and better thermal stability than DPD.

In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol

2021 ◽  
Vol 147 ◽  
pp. 111859
Author(s):  
Brianna J. Stubbs ◽  
Thanh Blade ◽  
Scott Mills ◽  
Jennifer Thomas ◽  
Xu Yufei ◽  
...  
Keyword(s):  
The Novel ◽  
In Vitro Stability ◽  
In Vivo Pharmacokinetics

scholarly journals Metal Complexes of a Novel Schiff Base Based on Penicillin: Characterization, Molecular Modeling, and Antibacterial Activity Study

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Narendra Kumar Chaudhary ◽  
Parashuram Mishra
Keyword(s):  
Thermal Stability ◽  
Antibacterial Activity ◽  
Schiff Base ◽  
Metal Complexes ◽  
Parent Drug ◽  
Molar Conductance ◽  
Kinetic Properties ◽  
Field Calculation ◽  
Tetrahedral Geometry

A novel Schiff base ligand of type HL was prepared by the condensation of amoxicillin trihydrate and nicotinaldehyde. The metal complexes of Co+2, Ni+2, Cu+2, and Zn+2 were characterized and investigated by physical and spectral techniques, namely, elemental analysis, melting point, conductivity, 1H NMR, IR, UV-Vis spectra, ESR, SEM, and mass spectrometry measurements. They were further analyzed by thermal technique (TGA/DTA) to gain better insight about the thermal stability and kinetic properties of the complexes. Thermal data revealed high thermal stability and nonspontaneous nature of the decomposition steps. The Coats-Redfern method was applied to extract thermodynamic parameters to explain the kinetic behavior. The molar conductance values were relatively low, showing their nonelectrolytic nature. The powder XRD pattern revealed amorphous nature except copper complex (1c) that crystallized in the triclinic crystal system. The EPR study strongly recommends the tetrahedral geometry of 1c. The structure optimization by MM force field calculation through ArgusLab 4.0.1 software program supports the concerned geometry of the complexes. The in vitro antibacterial activity of all the compounds, at their two different concentrations, was screened against four bacterial pathogens, namely, E. coli, P. vulgaris, K. pneumoniae, and S. aureus, and showed better activity compared to parent drug and control drug.

scholarly journals Bioactivity of vitamin E

2006 ◽  
Vol 19 (2) ◽  
pp. 174-186 ◽  
Author(s):  
Regina Brigelius-Flohé
Keyword(s):  
Vitamin E ◽  
Molecular Basis ◽  
Antioxidant Properties ◽  
The Body ◽  
The Novel ◽  
Transfer Protein ◽  
Almost All ◽  
Selection Of

More than 80 years after the discovery of the essentiality of vitamin E for mammals, the molecular basis of its action is still an enigma. From the eight different forms of vitamin E, only α-tocopherol is retained in the body. This is in part due to the specific selection of RRR-α-tocopherol by the α-tocopherol transfer protein and in part by its low rate of degradation and elimination compared with the other vitamers. Since the tocopherols have comparable antioxidant properties and some tocotrienols are even more effective in scavenging radicals, the antioxidant capacity cannot be the explanation for its essentiality, at least not the only one. In the last decade, a high number of so-called novel functions of almost all forms of vitamin E have been described, including regulation of cellular signalling and gene expression. α-Tocopherol appears to be most involved in gene regulation, whereas γ-tocopherol appears to be highly effective in preventing cancer-related processes. Tocotrienols appear to be effective in amelioration of neurodegeneration. Most of the novel functions of individual forms of vitamin E have been demonstrated in vitro only and require in vivo confirmation. The distinct bioactivities of the various vitamers are discussed, considering their metabolism and the potential functions of metabolites.

Synthesis and Anti-HIV Activity of Prodrugs Derived from Saquinavir and Indinavir

2000 ◽  
Vol 11 (2) ◽  
pp. 97-110 ◽  
Author(s):  
Audrey Farèse-Di Giorgio ◽  
Marielle Rouquayrol ◽  
Jacques Greiner ◽  
Anne-Marie Aubertin ◽  
Pierre Vierling ◽  
...  
Keyword(s):  
Transition State ◽  
Therapeutic Potential ◽  
Parent Drug ◽  
Inhibitory Potency ◽  
Respective Parent ◽  
Hiv Inhibition ◽  
Hydrolysis Of ◽  
Anti Hiv ◽  
In Vitro Stability

With a view to improving the pharmacological properties, safety and pharmacokinetic profiles of current protease inhibitors, the synthesis of various acyl-substituted saquinavir and indinavir prodrugs, their in vitro stability with respect to hydrolysis and their anti-HIV (LAI and HTLV IIIB) activity and cytotoxicity in CEM-SS and MT4 cells have been investigated. Hydrolysis of the ester bond and liberation of the active free drug was found to be crucial for HIV inhibition: the faster the hydrolysis, the closer the anti-HIV activity was to that of the respective parent drug. This is the case for most of the C-14-substituted indinavir and saquinavir derivatives (IC50 from 10 to 360 nM for ester half-lives of 90 min to 40 h). Concomitantly, the level of HIV inhibition is very low for the prodrugs for which hydrolysis is very slow. This is the case with the myristoyl or oleyl saquinavir esters, owing to the stable masking of the hydroxyl that is part of the peptidomimetic non-cleavable transition state isostere responsible for the inhibitory potency of saquinavir (and indinavir). In contrast, the anti-HIV activity of the monosubstituted C-8 indinavir prodrugs seems not to be correlated with their resistance to hydrolysis, as expected (the C-8 hydroxyl of indinavir is not involved in the transition state isostere). No cytotoxicity was detected for the indinavir and saquinavir prodrugs for concentrations as high as 10 or even 100 μM, thus indicating promising therapeutic potential.

scholarly journals Synthesis and Preclinical Evaluation of the Fibrin-Binding Cyclic Peptide 18F-iCREKA: Comparison with Its Contrasted Linear Peptide

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Yin Zhang ◽  
Lijuan Wang ◽  
Sirui Yu ◽  
Kongzhen Hu ◽  
Shun Huang ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Cyclic Peptide ◽  
Emission Tomography ◽  
The Novel ◽  
Preclinical Evaluation ◽  
Linear Peptide ◽  
Labeling Method ◽  
In Vitro Stability

Purpose. Cys-Arg-Glu-Lys-Ala (CREKA) is a pentapeptide which can target fibrin-fibronectin complexes. Our previous study has built a probe called iCREKA which was based on CREKA and has proved the feasibility and specificity of iCREKA by the fluorescence experiment. The purpose of this study is to achieve the 18F-labeled iCREKA and make preclinical evaluation of the 18F-iCREKA with comparison of its contrasted linear peptide (LP). Methods. CREKA, LP, and iCREKA were labeled by the Al18F labeling method, respectively. These 18F-labeled peptides were evaluated by the radiochemistry, binding affinity, in vitro stability, in vivo stability, micro-PET imaging, and biodistribution tests. Results. 18F-NOTA-iCREKA was stable both in vitro and in vivo. However, 18F-NOTA-CREKA and 18F-NOTA-LP were both unstable. The FITC or 18F-labeled iCREKA could be abundantly discovered only in matrix metalloproteinases- (MMPs-) 2/9 highly expressed U87MG cells, while the FITC or 18F-labeled LP could also be abundantly discovered in MMP-2/9 lowly expressed Caov3 cells. Biodistribution and micropositron emission tomography (PET) imaging revealed that the U87MG xenografts showed a higher uptake of 18F-NOTA-iCREKA than 18F-NOTA-LP while the Caov3 xenografts showed very low uptake of both 18F-NOTA-iCREKA and 18F-NOTA-LP. The tumor-to-muscle (T/M) ratio of 18F-NOTA-iCREKA (9.93 ± 0.42) was obviously higher than 18F-NOTA-LP (2.69 ± 0.35) in U87MG xenografts. Conclusions. The novel CREKA-based probe 18F-NOTA-iCREKA could get a high uptake in U87MG cells and high T/M ratio in U87MG mice. It was more stable and specific than the 18F-NOTA-LP.

Ester Prodrugs of Ketoprofen: Synthesis, In Vitro Stability, In Vivo Biological Evaluation and In Silico Comparative Docking Studies Against COX-1 and COX-2

2016 ◽  
Vol 13 (1) ◽  
pp. 41-57 ◽  
Author(s):  
Musa Ahmed ◽  
Faizul Azam ◽  
Abdul Gbaj ◽  
Abdulmottaleb E. Zetrini ◽  
Amna S. Abodlal ◽  
...  
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Cox 2 ◽  
In Vitro Stability ◽  
Ester Prodrugs ◽  
Cox 1

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Kinetics of Various 99mTc-Sn-Pyrophosphate Compounds in the Rat

1977 ◽  
Vol 16 (04) ◽  
pp. 157-162 ◽  
Author(s):  
C. Schümichen ◽  
B. Mackenbrock ◽  
G. Hoffmann
Keyword(s):  
Normal Saline ◽  
Half Life ◽  
Compound A ◽  
Short Half Life ◽  
Low Concentrations ◽  
The Stability ◽  
Kinetics Of ◽  
In Vitro Stability

SummaryThe bone-seeking 99mTc-Sn-pyrophosphate compound (compound A) was diluted both in vitro and in vivo and proved to be unstable both in vitro and in vivo. However, stability was much better in vivo than in vitro and thus the in vitro stability of compound A after dilution in various mediums could be followed up by a consecutive evaluation of the in vivo distribution in the rat. After dilution in neutral normal saline compound A is metastable and after a short half-life it is transformed into the other 99mTc-Sn-pyrophosphate compound A is metastable and after a short half-life in bone but in the kidneys. After dilution in normal saline of low pH and in buffering solutions the stability of compound A is increased. In human plasma compound A is relatively stable but not in plasma water. When compound B is formed in a buffering solution, uptake in the kidneys and excretion in urine is lowered and blood concentration increased.It is assumed that the association of protons to compound A will increase its stability at low concentrations while that to compound B will lead to a strong protein bond in plasma. It is concluded that compound A will not be stable in vivo because of a lack of stability in the extravascular space, and that the protein bond in plasma will be a measure of its in vivo stability.

A Simple and Inexpensive Clinical Whole Body Counter

1976 ◽  
Vol 15 (05) ◽  
pp. 248-253
Author(s):  
A. K. Basu ◽  
S. K. Guha ◽  
B. N. Tandon ◽  
M. M. Gupta ◽  
M. ML. Rehani
Keyword(s):  
The Body ◽  
Whole Body ◽  
Vitro Assay ◽  
Body Counter ◽  
Optimum Parameters ◽  
Whole Body Counter ◽  
Single Detector ◽  
Background Index ◽  
Iodide Crystal

SummaryThe conventional radioisotope scanner has been used as a whole body counter. The background index of the system is 10.9 counts per minute per ml of sodium iodide crystal. The sensitivity and derived sensitivity parameters have been evaluated and found to be suitable for clinical studies. The optimum parameters for a single detector at two positions above the lying subject have been obtained. It has been found that for the case of 131I measurement it is possible to assay a source located at any point in the body with coefficient of variation less than 5%. To add to the versatility, a fixed geometry for in-vitro counting of large samples has been obtained. The retention values obtained by the whole body counter have been found to correlate with those obtained by in-vitro assay of urine and stool after intravenous administration of 51Cr-albumin.

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