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Expert Opinion on Therapeutic Patents Oct 2014Deuterated versions of existing drugs can exhibit improved pharmacokinetic or toxicological properties due the stronger deuterium- carbon bond modifying their... (Review)
Review
INTRODUCTION
Deuterated versions of existing drugs can exhibit improved pharmacokinetic or toxicological properties due the stronger deuterium- carbon bond modifying their metabolism. There is great interest in the current state of development of this approach.
AREAS COVERED
This review covers recent US patent applications and prosecutions in this area that are based on beneficial modifications in metabolism of deuterated versions of existing drugs. The current state of 35 U.S.C. §103 'obviousness' rejections are emphasized, as is the development of strategies to overcome such rejections. Current trials and market considerations are also discussed.
EXPERT OPINION
Deuterated drugs collectively are worth at least US$1 billion. It would seem that the likelihood of obviousness rejections is increasing in this area. However, careful elucidation of metabolic outcomes from deuteration that would not be anticipated from the prior art, and are instead unexpected and unobvious, has enabled allowance. Showing that drug deuteration alters pharmacokinetics by mechanisms not currently part of the prior art surrounding deuterated drugs has also been successful. Development of these and other strategies, combined with developing the extensive base of issued patents will enable the field to remain commercially attractive for some time.
Topics: Deuterium; Drug Industry; Patents as Topic; Pharmacokinetics
PubMed: 25069517
DOI: 10.1517/13543776.2014.943184 -
The Journal of Nutrition Sep 2022Deuterium oxide (D2O) dilution is the criterion method for total body water (TBW) measurement, but results may vary depending on the specimen type, analysis method, and...
BACKGROUND
Deuterium oxide (D2O) dilution is the criterion method for total body water (TBW) measurement, but results may vary depending on the specimen type, analysis method, and analyzing laboratory. Bioelectrical impedance (BIA) estimates TBW, but results may vary by device make and model.
OBJECTIVES
We investigated the accuracy and precision of TBW estimates and how measurement conditions affected the accuracy of body composition using multicompartment body composition models.
METHODS
Eighty collegiate athletes received duplicate TBW measures acquired from 3 BIA devices (S10, SFB7, and SOZO) and from unique D2O combinations of specimen type (saliva, urine), analysis methodology [Fourier transform infrared spectrophotometry (FTIR), isotope-ratio mass spectrometry (IRMS)], and 3 different laboratories. TBW measures were substituted into 2-compartment (2C) and 5-compartment (5C) body composition models. Criterion measures were compared using Lin's concordance correlation coefficient cutoff of poor (<0.90), moderate (0.90-0.95), substantial (0.95-0.99), and almost perfect (>0.99).
RESULTS
Fifty-one participants (26 female) completed the protocol. Using IRMS saliva as the criterion TBW, all other measures produced a substantial or almost perfect agreement, except for SFB7 (poor) and SOZO (moderate). The 2C body composition measures using D2O and BIA produced poor agreement except for moderate agreement for lab 3 FTIR saliva. The 5C body composition measures using D2O produced a substantial agreement, whereas the BIA device S10 and SOZO had a moderate agreement, while the SFB7 had a poor agreement to the criterion. Test-retest precision varied between techniques from 0.3% to 1.2% for TBW.
CONCLUSIONS
Small differences in TBW measurement led to significant differences in 2C models. The 5C models partially mitigate differences seen in 2C models when different TBW measures are used. Interchanging TBW measures in multicompartment models can be problematic and should be performed with these considerations.
Topics: Athletes; Body Composition; Body Water; Deuterium; Deuterium Oxide; Electric Impedance; Female; Humans; Indicator Dilution Techniques
PubMed: 35665820
DOI: 10.1093/jn/nxac116 -
Blood Jun 2011
Topics: Animals; Deuterium; Humans; Kinetics; Models, Theoretical; Neutrophils
PubMed: 21636721
DOI: 10.1182/blood-2010-12-322271 -
Nature Communications Jun 2022Herein, a facile and general electroreductive deuteration of unactivated alkyl halides (X = Cl, Br, I) or pseudo-halides (X = OMs) using DO as the economical...
Herein, a facile and general electroreductive deuteration of unactivated alkyl halides (X = Cl, Br, I) or pseudo-halides (X = OMs) using DO as the economical deuterium source was reported. In addition to primary and secondary alkyl halides, sterically hindered tertiary chlorides also work very well, affording the target deuterodehalogenated products with excellent efficiency and deuterium incorporation. More than 60 examples are provided, including late-stage dehalogenative deuteration of natural products, pharmaceuticals, and their derivatives, all with excellent deuterium incorporation (up to 99% D), demonstrating the potential utility of the developed method in organic synthesis. Furthermore, the method does not require external catalysts and tolerates high current, showing possible use in industrial applications.
Topics: Catalysis; Deuterium
PubMed: 35773255
DOI: 10.1038/s41467-022-31435-9 -
Science (New York, N.Y.) Dec 2017Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of...
Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp carbon-hydrogen bonds in a single step, using isotopically labeled water (DO or TO) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of TO from T, providing access to high-specific-activity TO. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies.
Topics: Carbon; Catalysis; Deuterium; Deuterium Oxide; Hydrogen Bonding; Isotope Labeling; Ligands; Oxidation-Reduction; Pharmaceutical Preparations; Photochemical Processes; Tritium; Water
PubMed: 29123019
DOI: 10.1126/science.aap9674 -
Current Opinion in Structural Biology Oct 2014Hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS or DXMS) has emerged as an important tool for the development of small molecule therapeutics and... (Review)
Review
Hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS or DXMS) has emerged as an important tool for the development of small molecule therapeutics and biopharmaceuticals. Central to these advances have been improvements to automated HDX-MS platforms and software that allow for the rapid acquisition and processing of experimental data. Correlating the HDX-MS profile of large numbers of ligands with their functional outputs has enabled the development of structure activity relationships (SAR) and delineation of ligand classes based on functional selectivity. HDX-MS has also been applied to address many of the unique challenges posed by the continued emergence of biopharmaceuticals. Here we review the latest applications of HDX-MS to drug discovery, recent advances in technology and software, and provide perspective on future outlook.
Topics: Deuterium; Drug Discovery; Hydrogen; Mass Spectrometry; Pharmaceutical Preparations
PubMed: 25179005
DOI: 10.1016/j.sbi.2014.08.007 -
Drug News & Perspectives 2010The kinetic isotope effect has long been exploited by physical organic chemists to study reaction mechanisms due to its effect on reaction rates when cleavage of a... (Review)
Review
The kinetic isotope effect has long been exploited by physical organic chemists to study reaction mechanisms due to its effect on reaction rates when cleavage of a C-isotope bond is rate determining. Medicinal chemists have also used the deuterium kinetic isotope effect to slow the cytochrome P450 metabolism of the deuterated versions of drug candidates, with the first in vitro microsome studies of deuterated morphine appearing in the literature in the 1960s, and a deuterated alanine compound from Merck going all the way to phase IIb in the 1970s. The recent emergence of companies such as Concert Pharmaceuticals and Auspex Pharmaceuticals, based solely on the idea of deuterium-for-hydrogen versions of existing drugs, has reinvigorated the backers of the deuterium camp, and established the strategy as a viable low-risk approach to drug development. A history of the deuterium kinetic isotope effect is presented, along with examples of deuterated drugs that span 50 years, from 1960 to present day. Specific examples of compounds from the Concert and Auspex pipelines are also analyzed and the pros and cons of their approach are discussed.
Topics: Deuterium; Drug Discovery; Kinetics
PubMed: 20697607
DOI: 10.1358/dnp.2010.23.6.1426638 -
Proceedings of the National Academy of... Jan 1998With the advent of the new extragalactic deuterium observations, Big Bang nucleosynthesis (BBN) is on the verge of undergoing a transformation. In the past, the emphasis...
With the advent of the new extragalactic deuterium observations, Big Bang nucleosynthesis (BBN) is on the verge of undergoing a transformation. In the past, the emphasis has been on demonstrating the concordance of the BBN model with the abundances of the light isotopes extrapolated back to their primordial values by using stellar and galactic evolution theories. As a direct measure of primordial deuterium is converged upon, the nature of the field will shift to using the much more precise primordial D/H to constrain the more flexible stellar and galactic evolution models (although the question of potential systematic error in 4He abundance determinations remains open). The remarkable success of the theory to date in establishing the concordance has led to the very robust conclusion of BBN regarding the baryon density. This robustness remains even through major model variations such as an assumed first-order quark-hadron phase transition. The BBN constraints on the cosmological baryon density are reviewed and demonstrate that the bulk of the baryons are dark and also that the bulk of the matter in the universe is nonbaryonic. Comparison of baryonic density arguments from Lyman-alpha clouds, x-ray gas in clusters, and the microwave anisotropy are made.
Topics: Astronomical Phenomena; Astronomy; Deuterium; Evolution, Planetary; Hydrogen; Microwaves
PubMed: 9419322
DOI: 10.1073/pnas.95.1.42 -
Cancer Control : Journal of the Moffitt... 2021The effects of deuterium-depleted water (DDW) containing deuterium (D) at a concentration of 25 parts per million (ppm), 50 ppm, 105 ppm and the control at 150 ppm were...
The effects of deuterium-depleted water (DDW) containing deuterium (D) at a concentration of 25 parts per million (ppm), 50 ppm, 105 ppm and the control at 150 ppm were monitored in MIA-PaCa-2 pancreatic cancer cells by the real-time cell impedance detection xCELLigence method. The data revealed that lower deuterium concentrations corresponded to lower MiA PaCa-2 growth rate. Nuclear membrane turnover and nucleic acid synthesis rate at different D-concentrations were determined by targeted [1,2-C]-D-glucose fate associations. The data showed severely decreased oxidative pentose cycling, RNA ribose C labeling from [1,2-C]-D-glucose and nuclear membrane lignoceric (C24:0) acid turnover. Here, we treated advanced pancreatic cancer patients with DDW as an extra-mitochondrial deuterium-depleting strategy and evaluated overall patient survival. Eighty-six (36 male and 50 female) pancreatic adenocarcinoma patients were treated with conventional chemotherapy and natural water (control, 30 patients) or 85 ppm DDW (56 patients), which was gradually decreased to preparations with 65 ppm and 45 ppm deuterium content for each 1 to 3 months treatment period. Patient survival curves were calculated by the Kaplan-Meier method and Pearson correlation was taken between medial survival time (MST) and DDW treatment in pancreatic cancer patients. The MST for patients consuming DDW treatment (n = 56) was 19.6 months in comparison with the 6.36 months' MST achieved with chemotherapy alone (n = 30). There was a strong, statistically significant Pearson correlation (r = 0.504, p < 0.001) between survival time and length and frequency of DDW treatment.
Topics: Cell Proliferation; Deuterium; Female; Humans; Male; Nuclear Envelope; Pancreatic Neoplasms; RNA
PubMed: 33760674
DOI: 10.1177/1073274821999655 -
Journal of Chromatography. A Jan 2023Reversed-phase peptide separation in hydrogen deuterium exchange (HDX) mass spectrometry (MS) must be done with conditions where the back exchange is the slowest...
Reversed-phase peptide separation in hydrogen deuterium exchange (HDX) mass spectrometry (MS) must be done with conditions where the back exchange is the slowest possible, the so-called quench conditions of low pH and low temperature. To retain maximum deuterium, separation must also be done as quickly as possible. The low temperature (0 °C) of quench conditions complicates the separation and leads primarily to a reduction in separation quality and an increase in chromatographic backpressure. To improve the separation in HDX MS, one could use a longer gradient, smaller particles, a different separation mechanism (for example, capillary electrophoresis), or multi-dimensional separations such as combining ion mobility separation with reversed-phase separation. Another way to improve separations under HDX MS quench conditions is to use a higher flow rate where separation efficiency at 0 °C is more ideal. Higher flow rates, however, require chromatographic systems (both pumps and fittings) with higher backpressure limits. We tested what improvements could be realized with a commercial UPLC/UHPLC system capable of ∼20,000 psi backpressure. We found that a maximum flow rate of 225 µL/min (using a 1 × 50 mm column packed with 1.8 µm particles) was possible and that higher flow rate clearly led to higher peak capacity. HDX MS analysis of both simple and particularly complex samples improved, permitting both shorter separation time, if desired, and providing more deuterium recovery.
Topics: Hydrogen Deuterium Exchange-Mass Spectrometry; Deuterium; Deuterium Exchange Measurement; Mass Spectrometry; Peptides; Hydrogen
PubMed: 36586285
DOI: 10.1016/j.chroma.2022.463742