Discovery and\nPreclinical Characterization of Fulacimstat\n(BAY 1142524), a Potent and Selective Chymase Inhibitor As a New Profibrinolytic\nApproach for Safe Thrombus Resolution

Chymase is a serine-protease produced by mast cells.\nIn the past\nfew decades, its role in fibrotic diseases triggered the search for\norally available chymase inhibitors. Aiming at reducing adverse cardiac\nremodeling after myocardial infarction, our research efforts resulted\nin the discovery of fulacimstat (BAY 1142524). While clinical trials\ndid not demonstrate efficacy in this indication, the recent discovery\nof a new unexpected biological role of chymase spurred a revival of\ninterest in chymase inhibition: chymase was shown to inactivate plasmin\nwithin fibrin-rich clots. Chymase inhibitors are now considered as\npotential profibrinolytic drugs with low bleeding risk and therefore\nexceptional safety for the treatment of acute thrombosis settings\nsuch as stroke, pulmonary embolism, or venous thrombosis. This article\ndescribes the chemical optimization journey from a screening hit to\nthe discovery of fulacimstat (BAY 1142524), a selective chymase inhibitor\nwith a good safety profile, as well as its preclinical <i>in\nvitro</i> and <i>in vivo</i> characterization.