Discovery of GPR183 Agonists Based on an Antagonist Scaffold

The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca²⁺ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.     

A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp³ hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC₅₀ value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.     

Applications of Diglycolamide Based Solvent Extraction Processes in Spent Nuclear Fuel Reprocessing,Part 1: TODGA

Over the last decade there has been much interest in the applications of diglycolamide (DGA) ligands for the extraction of the trivalent lanthanide and actinide ions from PUREX high active raffinates or dissolved spent nuclear fuel. Of the DGAs, the N,N,N’,N’-tetraoctyldiglycolamide (TODGA) is the best known and most widely studied. A number of new actinide separation processes have been proposed based on extraction with TODGA. This review covers TODGA-based processes and extraction data, specifically focusing on how phase modifiers have been used to increase metal loading and thus enhance the operating process envelopes. Effects of third phase formation and the organic phase speciation are reviewed in this context. Relevant aspects of the extraction chemistry of important solvents (TODGA-modifier-diluent combinations) are described and their performances demonstrated by a consideration of the published flowsheet tests. It is seen that modifiers are successfully enabling the use of TODGA in actinide separation processes but to date the identification and testing of suitable modifiers has been rather empirical. There is a growing understanding of the fundamental chemistry occurring in the organic phase and how that affects extractant speciation and metal loading capacity but studies are still needed if TODGA-based flowsheets are to become an industrially deployable option for minor actinide (MA) recovery processes.     

Modeling aviation baggage screening security systems: a case study

Aviation security protects vital national interests, as well as passengers and aircraft. Key components of an aviation security system include baggage and passenger screening devices and operations. Determining how and where to assign (deploy) such devices can be quite challenging. Moreover, even after such systems are in place, it can be difficult to measure their effectiveness. This paper describes how discrete optimization models can be used to address these questions, based on three performance measures that quantify the effectiveness of airport baggage screening security device systems. These models are used to solve for optimal airport baggage screening security device deployments considering the number of passengers on a set of flights who have not been cleared using a security risk assessment system in use by the Federal Aviation Administration (i.e., passengers whose baggage is subjected to screening), the number of flights in this set, and the size of the aircraft for such flights. Several examples are provided to illustrate these results, including an example that uses data available from the Official Airline Guide.     

Application of novel extractants for actinide(III)/ lanthanide(III) separation in hollow-fibre modules

Separation tests using hollow-fibre modules were performed for the difficult selective extraction of trivalent actinides over fission lanthanides from acidic media. This article shows that with 2,6-di(5,6-dipropyl-1,2,4-triazin-3-yl)pyridine as the extractant, up to 94% americium could be extracted from 1.0 kmol/m³ HNO₃, with minimal lanthanide co-extraction. Using a synergistic mixture of bis(chlorophenyl)dithiophosphinic acid and tri-n-octyl phosphine oxide, tests were performed on extraction, lanthanide scrubbing and stripping. In the extraction test, up to 99.99% americium could be extracted from 0.5 kmol/m³ HNO₃, with approximately one third of the lanthanides being co-extracted. Mass transfer calculations using a consistent set of input data showed good agreement with the experiments.     

The hot blow forming of AZ31 Mg sheet: Formability assessment and application development

The hot blow forming of magnesium sheet offers significant opportunity for forming complex, lightweight parts for automotive applications. This paper characterizes the elevated-temperature formability of AZ31 magnesium sheet materials and the effect of processing conditions on the performance of these materials. In addition, magnesium sheet application development at General Motors Corporation is reviewed.     

Giga Security

The flow of information, within organizations, between networks, and from single users to other individuals and networks, is commonly at rates that only a few years ago were dreams. Earlier methods for the detection and prevention of malicious activities are anywhere from inefficient to unworkable with transmissions at the giga speeds that are prevalent today. This writing sets forth the problems and threats associated with these new high speed transmissions, and presents methodologies and systems for treating them.