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Rational Design of Renin Inhibitors
V. Dhanaraj * and J.B. Cooper† **
Birkbeck College, London, England
I. Introduction
Page 321
There has been much interest in the development of therapies for hypertension and associated heart
failure, which is a major cause of death in the western world. One of the key mediators in primary
hypertension is the plasma octapeptide angiotensin II (AII), which plays a major role by causing
vasoconstriction and stimulating aldosterone release, thereby increasing blood volume by its action on
the kidneys. Angiotensin II is produced by a proteolytic cascade—known as the renin-angiotensin
system—in which the aspartic proteinase renin catalyses the rate-limiting cleavage of angiotensinogen
produced by the liver to yield the decapeptide angiotensin I (AI). The subsequent removal of the
carboxy-terminal dipeptide from AI by angiotensin-converting enzyme (ACE), yielding AII, is the target
for a number of drugs that are effective for treating hypertension, hyperaldosteronism, and congestive
heart failure [1].
The development of potent low-molecular-weight orally active ACE inhibitors from natural and
synthetic metalloproteinase inhibitors has been rapid, due in part to the relative lack of specificity of this
enzyme. In contrast, renin cleaves only its natural substrate or very close analogs and although inhibition
of an enzyme more specific than ACE may be desirable for reducing side effects in vivo, the selectivity
of renin meant that during the early stages of drug development, potent inhibition required the use of
large peptide-based compounds. These were often poorly absorbed and susceptible to gastric proteolysis
and biliary excretion. Nevertheless, the commercial and clinical success of ACE inhibitors fueled
interest in the search for therapeutic renin drugs. Most inhibitors have been developed by elaboration of
the minimal substrate sequence (residues 6–13 of angiotensinogen), which exhibits weak competitive
inhibition, and replacement of the scissile bond with various nonhydrolysable surrogates, some of which
may be transition state analogues [2].
Current affiliation: University of Cambridge, Cambridge, England.
Current affiliation: University of Southhampton, Southhampton, England.
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