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Multi-Functional Monoamine Oxidase and Cholinesterase Inhibitors for the Treatment of Alzheimer’s Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Ireen Denya, Sarel F. Malan, Jacques Joubert
In a study by Denya et al. (2018) in vitro testing of indole-based compounds similar to ladostigil for ChE and MAO inhibitory activity was carried out using eeAChE, eqBuChE and hMAO enzymes. The assay results showed that the compounds were dual and non-selective inhibitors of the ChE enzymes. They all possessed IC50 values lower than 5 μM in the presence or absence of the propargylamine substitution on N1 of the indole. The compounds possessed good activity towards MAO–A and B and the presence of the urea moiety versus the carbamate moiety resulted in compounds that have comparably better inhibitory capacities than the carbamate linked compounds. In molecular modelling studies some interactions were observed between the indole ring and Trp 279 in AChE and Ille 199 in MAO, which showed that it probably plays a role in the inhibitory capacity of the compounds. Compound 18 had the best overall activity of all the tested compounds (Fig. 11.16). When compared to ladostigil, compound 18 demonstrated an AChE inhibitory capacity 9 times that of ladostigil and a 13-fold increase in MAO–B inhibition. Moreover, compound 18 also possesses superior MAO–A inhibitory capacity in vitro. It also proved to be more chemically stable compared to the carbamate-linked compound based on a 7-day forced degradation study (Denya et al., 2018).
CMC Requirements for Biological Products
Published in Shein-Chung Chow, Analytical Similarity Assessment in Biosimilar Product Development, 2018
Common errors include an insufficient number of lots, insufficient stability data, stability containers not representative of the drug substance container-closure system, absence of forced degradation data to identify stability indicating assays, and the absence of stability protocols.
Correlated analytical and functional evaluation of higher order structure perturbations from oxidation of NISTmAb
Published in mAbs, 2023
Tsega L. Solomon, Frank Delaglio, John P. Giddens, John P. Marino, Yihua Bruce Yu, Marc B. Taraban, Robert G. Brinson
One commonly applied forced degradation method is chemical oxidation. Oxidation of amino acids is one of the most prevalent post-translational chemical modifications that can occur in the cellular environment, during formulation of the therapeutic protein or in storage.8 A number of residues, including methionine (Met), cysteine, tryptophan, and histidine, are susceptible to oxidation in the presence of reactive oxygen species (ROS).9 Met oxidation, in particular, has been linked to alteration in mAb activity and stability, which has implications for drug quality and efficacy. This feature has made the mAb oxidation stress study a common pharmaceutical tool to evaluate the developability of drug candidates.10 One common oxidation method is to treat a mAb with hydrogen peroxide, a common ROS that primarily oxidizes Met residues via a nucleophilic substitution of the side-chain thiol to produce methionine sulfoxide (MetO) and in extreme excess cases, Met sulfone.11 Common analytical methods used to evaluate chemical oxidation include liquid chromatography (LC), cation exchange chromatography, and mass spectrometry.10,12–14 While these methods provide powerful tools for identifying and quantifying oxidation sites, in general they do not provide a readout of the effect of oxidation on the HOS of the drug. The one exception is hydrogen-deuterium exchange mass spectrometry, which can be correlated to HOS.15
Effects of the COVID-19 pandemic: new approaches for accelerated delivery of gene to first-in-human CMC data for recombinant proteins
Published in mAbs, 2023
Hervé Broly, Jonathan Souquet, Alain Beck
Developability assessments address not only the design of molecules, but also their suitability for manufacturing, storage, and administration. The developability assessment at the design stage of a new biological entity may lead to engineering out hot spots for degradation or undesired modifications to improve the manufacturability and the stability of a new product.21,22 In recent years, computational approaches with the support of advanced analytical tools have been developed to predict, for example, the propensity of a molecule to undergo self-interaction, aggregation and formation of particles, chemical modifications, such as oxidation and deamidation, propensity to cleavage by proteases, conformational stability, sequence-based isoelectric point, and changes affecting the electrical charge.23–32 These predictions could be further confirmed by carrying out forced degradation studies on the first grams of material produced that are traditionally used to identify product variants and degradation pathways and to support analytical method development.33,34 In that context, forced degradation studies help assess the criticality of quality attributes through a comprehensive understanding of their severity of impact, their process- or storage-driven variability (occurrence) and the testing strategy/method capability (detectability).35,36
Development and optimization of amphiphilic self-assembly into nanostructured liquid crystals for transdermal delivery of an antidiabetic SGLT2 inhibitor
Published in Drug Delivery, 2022
Nancy M. Lotfy, Mohammed Abdallah Ahmed, Nada M. El Hoffy, Ehab R. Bendas, Nadia M. Morsi
The formula of choice was further analyzed for chemical stability by a slightly modified validated reversed phase RP HPLC stability indicating method (Suneethal & Sharmila, 2015). The method was revalidated for linearity, accuracy, precision, robustness, selectivity and specificity. Forced degradation was also pursued under different stress conditions; namely, acid hydrolysis, alkali hydrolysis, oxidation and thermal degradation. Such conditions were attained by adding of 5 mL of 2 N sodium hydroxide, 2 N HCl and 20% H2O2 to 1 mL of the drug sample, and reflux for 30 min at 60 °C. Whereas, thermal degradation was done by heating the drug solution in an oven at 105 °C for 6 h. The working steps were carried out in isocratic mode using (Agilent-1260 Infinity, USA) HPLC apparatus, 0.1% orthophosphoric buffer:acetonitrile (53:47) were used as a mobile phase, C18 Hypersil BDS column (100 mm × 4.6 mm, 5 μ) was used. Column temperature was adjusted at 30 °C. Injection volume was 10 µL and flow rate was maintained at 0.85 mL/min. The measurements were taken at retention time of 11.3 min and 290 nm wavelength using photo diode array detector. Calibration curves of CFZ in the mobile phase solution were constructed.