Current therapy for cardiovascular disease is focused on the modulation of angiotensin II (ANG II) levels via the use of angiotensin-converting enzyme (ACE) inhibitors and/or ANG II receptor antagonists. It has been observed that ANG II is generated in the presence of ACE inhibitors. A substantial body of evidence suggests that chymase, a chymotrypsin-like serine protease of mast cells, is involved in the production of ANG II by an ACE-independent pathway and may play a significant role in vascular hypertrophy, hypertension, ischemic heart disease and congestive heart failure. Inhibitors of chymase are of potential therapeutic value in cardiovascular disease either by themselves or in combination with ACE inhibitors. This proposal is built on the availability of three unique resources. These three resources are: (l) A novel heterocyclic template; (2) The availability of sufficient quantities of recombinant human chymase; and (3) Assays for specificity using a large panel of proteases. Combined they will lead to the discovery of inhibitors of human chymase useful in the treatment of cardiovascular disease. PROPOSED COMMERCIAL APPLICATIONS: Specific inhibition of human heart chymase may be of value in the treatment of hypertension, congestive heart failure and related ailments.
