Identification and elaboration of fluorine containing inhibitors of proline rich tyrosine kinase and endothelial nitric oxide synthase

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Type 2 Diabetes Mellitus, where our bodies do not produce enough insulin, or the insulin that is produced does not function properly,is an increasingly common disorder. Around four million people in the UK are affected by type 2 diabetes and it is estimated that 14 billion pounds is spent a year on treating diabetes and its complications in the UK alone. People with diabetes are up to five times more likely to have cardiovascular disease and their quality of life is likely to be more affected by it than people who don't have the disease.This is in part due to diabetes changing the cells that line your blood vessels, leading more toxic molecules in them and a decrease in beneficial molecules such as nitric oxide. We have recently shown that increased levels of a protein called PYK2 is found in the bodies of people with type 2 diabetes. This protein reduces nitric oxide levels by preventing the protein that makes nitric oxide (called eNOS) from working. We will use fragment based ligand discovery to identify fragments which modulate the interaction between eNOS and PYK2. These can be elaborated into small molecules. Fragment based ligand discovery allows greater sampling of chemical space compared with traditional screening techniques, even with a modestly sized compound library. Because of the weaker binding affinities typically exhibited by fragments, sensitive biophysical techniques such as Nuclear Magnetic Resonance are required to detect the binding event. The use of fluorine containing fragments for Nuclear Magnetic Resonance screening allows increased throughput versus fragments without a fluorine in as the spectra obtained are simplified and easier to read. This gives us the ability to screen mixtures of samples without spectral overlap, allowing cocktails of fragments, with around 10 compounds per tube, to be characterised, maximising efficiency.This newly discovered interaction offers a novel way to address the cardiovascular complications of type 2 diabetes. The new 4 channel Nuclear Magnetic Resonance probe at Leeds allows fluorine containing fragment screening for the first time. Results from this work will pave the way to develop therapies to treat type 2 diabetes targeting a previously unexploited pathway.