Development and design of specific inhibitors of angiotensin-converting enzyme.
Captopril is a remarkably effective new antihypertensive drug designed and developed as a potent and specific inhibitor of angiotensin-converting enzyme, a zinc metallopeptidase that participates in the synthesis of a hypertensive peptide, angiotensin II, and in the degradation of a hypotensive peptide, bradykinin. Earlier studies with a snake venom peptide (teprotride or SQ 20881) that could be administered only by injection demonstrated that specific inhibitors of angiotensin-converting enzyme could be highly effective as antihypertensive drugs, and helped to clarify the specificity and mechanism of action of the enzyme. A hypothetical model of the active center of angiotensin-converting enzyme based on its presumed analogy to the well characterized zinc metallopeptidase carboxypeptidase A was used to guide logical sequential improvements of a weakly active prototype inhibitor that led eventually to the highly optimized structure of captopril. The hypothetical working model of the active site of angiotensin-converting enzyme used to develop captopril continues to provide a firm basis for development of new types of specific inhibitors of this biologically important enzyme.
D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001794:Blood Pressure; D002216:Captopril / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D011392:Proline / Q000031:analogs & derivatives / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000187:drug effects; D013386:Succinates / Q000627:therapeutic use; D013722:Teprotide / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D013386:Succinates; C034375:succinylproline; C000249:benzylsuccinic acid; D011392:Proline; D002216:Captopril; D013722:Teprotide; D007703:Peptidyl-Dipeptidase A