CHYMASE - ITS PATHOPHYSIOLOGICAL ROLES AND INHIBITORS

Chymase is a chymotrypsin-type serine protease mainly localized in mas t cells (MCs). Human, primate, and dog chymase generate angiotensin II (Ang II) from Ang I, while mouse and rat chymases degrade Ang II. It is suggested that chymase generating Ang Il might be an alternative An g II-forming enzyme to angiotensin-converting enzyme (ACE) in the reni n-angiotensin system in tissues, but not in blood, and cause hypertrop hy and remodeling of cardiovascular tissues. Chymase also degrades ext racellular matrix, and processes procollagenase, inflammatory cytokine s and other bioactive peptides. As a result, chymase plays important r oles in inflammatory tissues through its proteolytic activities to cau se tissue remodeling, that is, a chymase inhibitor may have the abilit y to prevent diseases caused by the above inflammatory reactions. The investigation of chymase inhibitors by pharmaceutical companies has yi elded peptide and peptide mimetic inhibitors. We also found potent non -peptide low molecular inhibitors. However, the in vivo Functions of c hymase have not been verified so far by applying a chymase inhibitor t o in vivo pathological models. In this article, we overview the pathop hysiological roles of chymase and chymase inhibitors proposed to date, and discuss the structure-activity relationships of substituted 3-phe nylsulfonyl-1-phenylimidazolidine-2,4-dione derivatives.