Renin Inhibitors: Discovery and Development An Overview and Perspective

: Pharmacological suppression of the renin angiotensin system (RAS) by inhibiting angiotensin-converting enzyme (ACE), both as monotherapy and in conjunction with other conventional agents, has been proven to be an effective therapeutic approach to the treatment of hypertension and congestive heart failure. Renin is the enzyme that catalyzes the first and rate limiting step, preceding the involvement of ACE, in the production of the potent pressor hormone angiotensin II (Ang II). Unlike ACE, which has multiple substrates, renin is selective for a single naturally occurring substrate, angiotensinogen. Interruption of the generation of ANG II by renin inhibitors at the highly specific, initial step of the cascade may have therapeutic advantages over ACE inhibitors and other antihypertensive agents with less precise mechanisms of action, by producing fewer clinical side effects. Exciting advances in the discovery of renin inhibitors have led to the synthesis of potent, dipeptide inhibitors of renin, which have been shown in the laboratory to be efficacious hypotensive agents when administered intravenously. Although there are recently reported compounds that demonstrate some degree of oral activity, efforts to enhance bioavailability are presently underway in order to develop orally active therapeutic agents. The development of renin inhibitors will provide target-specific agents for the treatment of various cardiovascular disorders, and will serve as invaluable tools to study the role of the RAS in regulating blood pressure and fluid volume. An overview of the progress in the discovery and development of renin inhibitors is presented.