CHAPTER 28:“Daring to be Different”: The Discovery of Ticagrelor

On Christmas Eve 2010, the first pack of a new oral anti-platelet agent, ticagrelor (BRILINTA®, BRILIQUE™), was dispensed. This case study describes the scientific and human factors underpinning the discovery of this orally-bioavailable, direct acting, P2Y12 antagonist. The P2Y12 receptor mediates sustained platelet aggregation to ADP, and the ADP/P2Y12 axis plays a key role in platelet-mediated thrombosis. We describe a journey starting from ATP, the natural P2Y12 antagonist—characterised by low potency, poor selectivity, short half-life, no oral bioavailability—and culminating in the realisation of ticagrelor. We describe the steps leading to the potent, selective ATP analogue, cangrelor, an intravenous P2Y12 antagonist with rapid onset and offset, designed for use in the acute hospital setting. Then, against the background of growing evidence for the clinical importance of P2Y12 antagonism, we outline the 5 year journey from cangrelor to ticagrelor. The challenge of introducing oral bioavailability and long duration of action into a triphosphate starting point is broken down into distinct phases, each associated with a landmark finding. For each phase we outline the key challenges, strategies and achievements and highlight the key themes, learnings and ways of working that enabled ultimate success.