enalapril and is a lysine derivative of enalaprilat. Lisinopril and captopril are currently
the only two ACE inhibitors in clinical use that are not prodrugs. The remainder of the
ACE inhibitors were developed by varying the ring system of the C-terminal amino
acid. The pyrrolidine ring system used in captopril, enalapril, and lisinopril was replaced
with larger bicyclic or spiro ring systems. This led to compounds such as moexipril
(5.139), perindopril (5.140), quinapril (5.141), ramipril (5.142), and trandolapril
(5.143). Despite many clinical similarities, these agents differ in their absorption, dosing
with other drugs, and duration of actions; for example, quinapril has a t1/2of 3 hours
whereas ramipril has a t1/2of 13–17 hours. The quest for ACE inhibitors devoid of the
sulfhydryl group also led to the evaluation of phosphonate-containing inhibitors, on the
basis of the notion that phosphinic acid is bioisosterically equivalent to sulfhydryl and
carboxylate groups in terms of Zn^2 +chelation. This lead to the development of fosinopril
(5.144) as a prodrug that is hydrolyzed by liver enzymes to the bioactive fosinoprilat.
Clinically, ACE inhibitors decrease vascular smooth muscle tone in arterioles and
promotenatriuresis(urinary secretion of Na+) without increasing heart rate; accord-
ingly, ACE inhibitors not only treat hypertension but also decrease morbidity associated
with congestive heart failure. ACE inhibitors may also delay the progression of diabetes-
associated kidney damage.
ACE inhibitors were designed to block the conversion of angiotensin I to angiotensin II.
However, they also inhibit the degradation of other peptides including bradykinin, sub-
stance P, and enkephalins. This inhibition of bradykinin metabolism causes ACE-
related side effects, including cough and angioedema.
5.21.2.3 Angiotensin Receptor Antagonists
Angiotensin receptor antagonists were developed through modification of the
angiotensin molecule. The most effective compound is the [Sar^1 ,Val^5 , Ala^8 ] angiotensin II,
called saralasin (5.145) (sar =sarcosine=N-methylglycine). Unfortunately, the peptidic
HORMONES AND THEIR RECEPTORS 375