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

目前用于具有动脉血栓形成风险的患者的治疗遭受次优功效并且携带出血风险的显著增加。本发明的目的是发现阻断血小板表面受体，血小板糖蛋白VI（GPVI）的化合物，该受体参与血栓形成，并且有充分的证据表明抑制将证明是有效的而不增加出血的风险。这将使患者得到更安全的治疗，并使高风险患者能够安全地增加剂量，而不像目前的药物在疗效和出血风险之间的治疗指数较窄。患者也有可能与抗凝剂联合给药，以进一步提高疗效（由于所用药物相关的出血风险，目前这种情况受到限制）。该项目的最终目标是生产一种口服的每日一次或两次的治疗方法。利兹大学的研究小组已经确定了一系列GPVI的小分子抑制剂，这些抑制剂在血小板活化和聚集试验以及在流动条件下进行的全球血栓形成试验中显示出与GPVI结合的证据。本申请中提出的工作计划旨在优化命中以改善功效、结合亲和力和“药物样”性质。此外，我们的目标是生成一种领先抑制剂的高分辨率配体-蛋白质结合晶体结构，以进一步支持化合物系列的优化。该奖项的交付成果将是一系列具有强大结构活性关系的领先化合物，以及与准备吸引后续投资和进一步开发的概况相一致的合适的效力和“药物样”性质。

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.