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 sp³ carbon-hydrogen bonds in a single step, using isotopically labeled water (D₂O or T₂O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T₂O from T₂, providing access to high-specific-activity T₂O. 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.
Covering: 1981 to 2019
Natural products continue to play a major role in drug discovery, with half of new chemical entities based structurally on a natural product. Herein, we report a cheminformatic ...analysis of the structural and physicochemical properties of natural product-based drugs in comparison to top-selling brand-name synthetic drugs, and a selection of chemical probes recently discovered from diversity-oriented synthesis libraries. In this analysis, natural product-based drugs covered a broad range of chemical space based on size, polarity, and three-dimensional structure. Natural product-based structures were also more prevalent in top-selling drugs of 2018 compared to 2006. Further, the drugs clustered well according to biosynthetic origins, but less so based on therapeutic classes. Macrocycles occupied distinctive and relatively underpopulated regions of chemical space, while chemical probes largely overlapped with synthetic drugs. This analysis highlights the continued opportunities to leverage natural products and their pharmacophores in modern drug discovery.
Cheminformatic analyses illustrate that drugs from natural product-based and synthetic origins have distinctive structural and physicochemical features. These drugs also cluster by biosynthetic origin and, to some extent, by therapeutic class.
Early clinical findings are reported for subjects implanted with the Vibrant Med-El Soundbridge® (VSB) device. The present criteria for the VSB, limiting its application to patients with normal ...middle ear function, have been extended to include patients with ossicular chain defects. Seven patients with severe mixed hearing loss were implanted with the transducer placed onto the round window. All had undergone previous surgery: six had multiple ossiculoplasties, and one had the VSB crimped on the incus with unsuccessful results. Round window implantation bypasses the normal conductive path and provides amplified input to the cochlea. Post-operative aided thresholds of 30 dB HL were achieved for most subjects, as compared with unaided thresholds ranging from 60-80 dB HL. Aided speech reception thresholds at 50% intelligibility were 50 dB HL, with most subjects reaching 100% intelligibility at conversational levels, while unaided thresholds averaged 80 dB HL, with only one subject reaching 100% intelligibility. These results suggest that round window implantation may offer a viable treatment option for individuals with severe mixed hearing losses who have undergone unsuccessful ossiculoplasties.
The G-protein-coupled receptors GPR81, GPR109A, and GPR109B share significant sequence homology and form a small group of receptors, each of which is encoded by clustered genes. In recent years, ...endogenous ligands for all three receptors have been described. These endogenous ligands have in common that they are hydroxy-carboxylic acid metabolites, and we therefore have proposed that this receptor family be named hydroxy-carboxylic acid (HCA) receptors. The HCA(1) receptor (GPR81) is activated by 2-hydroxy-propanoic acid (lactate), the HCA(2) receptor (GPR109A) is a receptor for the ketone body 3-hydroxy-butyric acid, and the HCA(3) receptor (GPR109B) is activated by the β-oxidation intermediate 3-hydroxy-octanoic acid. HCA(1) and HCA(2) receptors are found in most mammalian species, whereas the HCA(3) receptor is present only in higher primates. The three receptors have in common that they are expressed in adipocytes and are coupled to G(i)-type G-proteins mediating antilipolytic effects in fat cells. HCA(2) and HCA(3) receptors are also expressed in a variety of immune cells. HCA(2) is a receptor for the antidyslipidemic drug nicotinic acid (niacin) and related compounds, and there is an increasing number of synthetic ligands mainly targeted at HCA(2) and HCA(3) receptors. The aim of this article is to give an overview on the discovery and pharmacological characterization of HCAs, and to introduce an International Union of Basic and Clinical Pharmacology (IUPHAR)-recommended nomenclature. We will also discuss open questions regarding this receptor family as well as their physiological role and therapeutic potential.
To develop a reliable and objective fitting method for use with young children with an auditory brainstem implant (ABI).
Subjects were 17 young children implanted with an ABI with the mean age 2 ...years and 4 months (8–64 months). Evoked auditory brainstem response (eABR) measurements were performed intraoperatively and at activation in order to record the auditory response and non-auditory side effects. Each child was tested to observe any subjective responses to the electric stimuli and non-auditory side effects. All children were fitted based on the postoperative eABR. The minimum follow up time was 12 months.
Intraoperatively an eABR could be obtained in all children. The responses were recordable from 75–100% of all electrodes. At initial stimulation eABR were recordable in all children. The eABR was obtained in 79.7% of all electrodes (25–100%) with a mean eABR threshold of 22.3 nC. eABR without any non-auditory stimulation was recorded on all electrodes in 11 children. Mixed eABR and non-auditory responses were recorded on 2–6 electrodes in 6 children. The subjective auditory responses for at least 1 electrode were noted in 15 children. In the 2 remaining cases the auditory response was obtained only when the device was activated. In all children the subjective responses were within the estimated dynamic range for each electrode. Each child was able to accept up to 100% of volume of the created map. The non-auditory response was observed only on children and electrodes with mixed eABR and non-auditory responses. The mean CAP score at 6 months after the activation was 2.4 (1–4).
eABR seems to be a reliable tool to judge ABI electrode placement and a reliable method for fitting of young children with an ABI. The data suggest that eABR-based fitting helps children to more quickly achieve auditory perception and development.
Emergence of bacterial resistance is a major issue for all classes of antibiotics; therefore, the identification of new classes is critically needed. Recently we reported the discovery of ...platensimycin by screening natural product extracts using a target-based whole-cell strategy with antisense silencing technology in concert with cell free biochemical validations. Continued screening efforts led to the discovery of platencin, a novel natural product that is chemically and biologically related but different from platensimycin. Platencin exhibits a broad-spectrum Gram-positive antibacterial activity through inhibition of fatty acid biosynthesis. It does not exhibit cross-resistance to key antibiotic resistant strains tested, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant ENTEROCOCCI: Platencin shows potent in vivo efficacy without any observed toxicity. It targets two essential proteins, β-ketoacyl-acyl carrier protein (ACP) synthase II (FabF) and III (FabH) with IC₅₀ values of 1.95 and 3.91 μg/ml, respectively, whereas platensimycin targets only FabF (IC₅₀ = 0.13 μg/ml) in S. aureus, emphasizing the fact that more antibiotics with novel structures and new modes of action can be discovered by using this antisense differential sensitivity whole-cell screening paradigm.
GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists ...are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The modified New Brunswick Laboratory (NBL) Davies and Gray titrimetry method uses potassium dichromate standard 136-f from the National Institute of Standards and Technology for calibration. ...However, the presence of chromium in the resulting waste stream makes the disposal of waste from this procedure costly. The Actinide Analytical Chemistry (C-AAC) group at Los Alamos National Laboratory investigated and transitioned to a cerium based titrant as an alternative. We present the first long-term analytical study using this ceric-based titration method and compare it with NBL results based on the more-widely used dichromate titrimetric method.
Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density ...lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D₂, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.
Through assay analysis into an excess of 1M H2SO4 at fixed temperature a technique has been developed for uranium concentration analysis by visible absorption spectroscopy over an assay concentration ...range of 1.8–13.4mgU/g. Once implemented for a particular spectrophotometer and set of spectroscopic cells this technique promises to provide more rapid results than a classical method such as Davies-Gray (DG) titration analysis. While not as accurate and precise as the DG method, a comparative analysis study reveals that the spectroscopic method can analyze for uranium in well characterized uranyl(VI) solution samples to within 0.3% of the DG results. For unknown uranium solutions in which sample purity is less well defined agreement between the developed spectroscopic method and DG analysis is within 0.5%. The technique can also be used to detect the presence of impurities that impact the colorimetric analysis, as confirmed through the analysis of ruthenium contamination. Finally, extending the technique to other assay solution, 1M HNO3, HCl and Na2CO3, has also been shown to be viable. Of the four aqueous media the carbonate solution yields the largest molar absorptivity value at the most intensely absorbing band, with the least impact of temperature.
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•A visible absorption spectroscopy uranium analysis technique.•Uranium analysis to within 0.3% of results obtained by Davies-Gray analysis.•Technique sensitive to impurities.
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