Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3‑Kinase δ for the Treatment of Respiratory Disease

Optimization of lead compound <b>1</b>, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates <b>2</b> (GSK2269557) and <b>3</b> (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds <b>2</b> and <b>3</b> are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3‑Kinase δ for the Treatment of Respiratory Disease

Optimization of lead compound <b>1</b>, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates <b>2</b> (GSK2269557) and <b>3</b> (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds <b>2</b> and <b>3</b> are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation

Preparation for commissioning of materials detritiation facility at Culham Science Centre

The Materials Detritiation Facility has been designed to thermally treat solid non-combustible radioactive waste produced during operations of the Joint European Torus (JET) that is classified as Intermediate Level Waste in the UK due to its tritium inventory (> 12 kBq/g). The waste will be thermally treated in a retort furnace at temperatures up to 1000 degrees C under a flowing air atmosphere to reduce its tritium inventory sufficiently to allow its disposal at a lower waste category via existing disposal routes. The gaseous flow from the furnace will be processed via a bubbler system, where released tritium will be trapped in water. Commissioning of the facility will be divided into two main parts: inactive and active. The main purpose of the inactive commissioning is to verify that all components and safety systems of the facility are installed, tested and operated properly and within their operational limits. Several trials of the furnace with non-radioactive materials will be performed to verify its temperature profile, and to verify operation of the gaseous process line. During the active commissioning, small amounts of tritium-contaminated material will be introduced into the facility and used for active trials. The tritium inventory in this material has been selected based on the As low as reasonably practicable (ALARP) principle, to ensure that the activity levels are sufficient to fully test the control instrumentation and pose minimal risk to operators during commissioning. Overall, four active trials will be performed with carbon-based and Inconel materials with total tritium inventories of 1MBq, 3GBq, 20GBq and 26GBq. Tritium levels in the bubblers as well as in aerial discharge from the facility will be monitored. Furthermore, all materials used in the active trials will be sampled and analyzed to verify the performance of the process and confirm that a major part of tritium inventory can be removed from materials by the process