Identification of small molecule GPVI inhibitors as anti-platelet agents for the treatment of thrombosis with minimal bleeding risk

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Current treatments for patients who have a risk of arterial thrombosis suffer from sub-optimal efficacy and carry a significant increase in the risk of bleeding. The objective of this proposal is to discover compounds which block a platelet surface receptor, platelet glycoprotein VI (GPVI), which is involved in thrombosis, and for which there is good evidence that inhibition will prove effective without increase the risk of bleeding. This will allow patients to be treated more safely and enable safe dose escalation in high-risk patients, unlike current medicines that have a narrower therapeutic index between efficacy and risk of bleeding. Patients will also have the potential to be co-administered with an anticoagulant agent to further improve efficacy (a scenario that is currently limited due to the bleeding risks associated with the agents used). The eventual aim of the programme is to produce an orally administered once-or-twice daily treatment.The team at the University of Leeds have identified a series of small molecule inhibitors of GPVI which demonstrate evidence of binding at GPVI and efficacy in platelet activation and aggregation assays, as well as a global thrombosis assay performed under flow conditions. The work plan proposed within this application is aimed at optimising the hits for improvement in efficacy, binding affinity and 'drug-like' properties. Additionally, we aim to generate a high-resolution ligand-protein bound crystal structure of a leading inhibitor to further support optimisation of the compound series.The deliverable of the award will be a lead series of compounds possessing robust structure activity relationships, and suitable potency and 'drug-like' properties consistent with a profile ready to attract follow-on investment and further development.