Discovery and Preclinical Characterization of Fulacimstat (BAY 1142524), a Potent and Selective Chymase Inhibitor As a New Profibrinolytic Approach for Safe Thrombus Resolution

Chymase is a serine-protease produced by mast cells.
In the past
few decades, its role in fibrotic diseases triggered the search for
orally available chymase inhibitors. Aiming at reducing adverse cardiac
remodeling after myocardial infarction, our research efforts resulted
in the discovery of fulacimstat (BAY 1142524). While clinical trials
did not demonstrate efficacy in this indication, the recent discovery
of a new unexpected biological role of chymase spurred a revival of
interest in chymase inhibition: chymase was shown to inactivate plasmin
within fibrin-rich clots. Chymase inhibitors are now considered as
potential profibrinolytic drugs with low bleeding risk and therefore
exceptional safety for the treatment of acute thrombosis settings
such as stroke, pulmonary embolism, or venous thrombosis. This article
describes the chemical optimization journey from a screening hit to
the discovery of fulacimstat (BAY 1142524), a selective chymase inhibitor
with a good safety profile, as well as its preclinical in
vitro and in vivo characterization.