Historical Vignettes in Heart Failure

Abstract

In describing the development of captopril and related antihypertensive drugs, we hope to resurrect a more specific meaning for the term drug design, namely, the logical process whereby molecules are constructed for precise fit with a macromolecular receptor. Thus defined, drug design requires direct or indirect knowledge of the nature of the receptor, which in this case is the active center of a peptidase known historically as angiotensin-converting enzyme (ACE). We believe that the development of captopril and related ACE inhibitors truly merits the use of the term drug design and that the therapeutic usefulness and specificity of the resulting drugs are a direct consequence of logical design. Captopril was developed first and foremost as a highly specific enzyme inhibitor; its antihypertensive activity was a consequence of this specific primary action.1 The discovery of ACE inhibitors marks the beginning of a new era in the treatment of cardiovascular diseases and more specifically in the treatment of heart failure. This introduces the concept of drug design and the general steps that culminated in the development of captopril. David Cushman (November 15, 1939–August 14, 2000) and Miguel Ondetti (May 14, 1930–August 23, 2004) from the Squibb Institute for Medical Research played a major role on the discovery of captopril and received in 1999 the Lasker Award for “developing an innovative approach to drug design based on protein structure and using it to create the ACE inhibitors, powerful oral agents for the treatment of high blood pressure, heart failure, and diabetic kidney disease.” A more detailed report on the steps that were taken in the discovery of captopril will be included in the next few historical vignettes. Hector O. Ventura, MD, Editor From the Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA Reference