People with a high risk of suffering from a heart attack or stroke often take drugs that prevent formation of clots in their blood vessels. These drugs have a narrow so-called therapeutic window: Dosages that are high enough to effectively limit harmful clotting can also increase a person’s risk of life-threatening bleeding. A team of researchers at Bristol-Meyers Squibb and the University of Montreal reports a new strategy that could widen that window (Sci. Transl. Med. 2017, DOI: 10.1126/scitranslmed.aaf5294). The enzyme thrombin plays a key role in activating platelet cells to start the clotting process. One of its functions is to turn on protease-activated receptors (PARs) by cutting off a bit of the N-terminus of the proteins. The drug vorapaxar works by turning off one member of that family, PAR1. The BMS-led team decided to investigate the potential of targeting the less studied PAR4. The researchers screened 1.1 million small molecule compounds to find one that blocked the receptor. Chemists optimized the resulting imidazothiadiazole compound to produce BMS986120. This compound was more effective in reducing clotting in cynomolgus monkeys and had a lower bleeding risk than did the approved drug clopidogrel. BMS has started a phase II clinical trial with a related molecule, BMS986141.