Medicinal Chemistry

5.21.1 Characterization of the Renin–Angiotensin System

Angiotensinogen (pre-proangiotensin) is produced by the liver; it is a glycoprotein with a
molecular weight of 57,000. Its production is under endocrine control by adrenocorticoids,
thyroid hormones, and estrogens (with the latter being prominent during pregnancy).
Renin, a highly specific endopeptidase (aspartyl protease), is a glycoprotein composed
of 340 amino acids; it is biosynthesized in the kidneys. It cleaves angiotensinogen
between leucine residue 10 and valine residue 11 to yield the bioinactive decapeptide
angiotensin I. Renin has a precursor, prorenin, which seems to be activated by pepsin
or trypsin. Prorenin has a molecular weight of about 60,000. Renin secretion is strictly
regulated by (1) renal vascular baroreceptors that sense the vessel wall tension in arte-
rioles; (2) Na+or Cl−receptors; (3) an angiotensin feedback mechanism; and (4) the
CNS, through catecholamines.
Angiotensin II, the octapeptide cleavage product of angiotensin I, is produced by
angiotensin-converting enzyme (ACE).ACE, a widely distributed exopeptidase that is
most abundant in the lungs and kidneys, is a glycoprotein containing a Zn^2 −ion; it is a
peptidyl dipeptidase that converts angiotensin I to angiotensin II by cleaving off the
C-terminal His-Leu dipeptide. Angiotensin II is a strong vasoconstrictor, and its effect
depends on its C-terminal Phe^8 residue. If this terminal amino acid is replaced by any
aliphatic amino acid, the activity of the hormone is lost; replacement by threonine leads
to antagonist action. The physiological effects of angiotensin II are widespread: in arte-
rioles, it causes smooth muscle contraction, elevating the blood pressure with a potency
40 times that of norepinephrine; in the autonomic nervous system, it causes the release
of epinephrine and norepinephrine from the adrenal medulla; in the adrenal cortex, it
stimulates the biosynthesis of aldosterone; in the kidneys, it causes renal vasoconstric-
tion, sodium reabsorption, and inhibition of the release of renin; in the central nervous
system, it stimulates drinking, and increases the secretion of vasopressin and ACTH.
Angiotensin II mediates its bioactivity via interaction with angiotensin (AT)
receptors. Two distinct receptor subtypes have been identified: AT 1 and AT 2. These
receptors are integral membrane proteins. The relative concentrations of the two recep-
tors differ from tissue to tissue; the AT 1 receptor dominates in vascular smooth muscle.
Thus, most of the pharmacological effects of angiotensin II are mediated via the AT 1
receptor, a G-protein-coupled receptor, leading to the generation of inositol triphos-
phate and diacylglycerol.

5.21.2 Inhibitors of the Renin–Angiotensin System

There are several points in the renin–angiotensin system that have proven to be amenable
to inhibition. Renin, angiotensin-converting enzyme, and the angiotensin receptors are
the most important sites of regulation.

5.21.2.1 Renin Inhibitors

Renin inhibitors have been found among naturally occurring phospholipids and
synthetic phosphatidylethanolamine derivatives. Pepstatin (5.131), isolated from
Streptomycesstrains, is a pentapeptide with an acylated N-terminus and the unusual
4-amino-3-hydroxy-6-methylheptanoic acid (AHMH) residues. It is a general protease

372 MEDICINAL CHEMISTRY