with a concomitant and dramatic hypotensive effect. Modification of these peptides
may lead to the discovery of more active and stable analogs for the treatment of edema
in congestive heart failure or renal insufficiency. Moreover, since natriuretic peptides
may play a role in actually preventing the development of hypertension (rather than
merely lowering blood pressure once hypertension has developed), this family of
peptides may be of future value in drug design related to therapies for hypertension.
Since hypertension is the most common cardiovascular disease, drug design and devel-
opment for treating high blood pressure is an extremely important endeavor within
medicinal chemistry.
5.23 Peptide Hormones and the Design of Drugs for Hypertension
The “bottom line” in medicinal chemistry is to design a molecule with the properties of
a drug (see chapter 1) to fit a macromolecule with the properties of a receptor (see
chapter 2) by exploiting a variety of design and optimization processes (see chapter 3).
From both a philosophical and a practical perspective, the overall process of drug
design may be pursued by either of two very broad approaches. In the first approach
(one target–multiple disease approach), one selects a single druggable targetand then
designs therapeutic molecules for pathological process(es) implicated in that target. For
instance, if the voltage-gated Na+channel were selected as the target, then drugs
designed to target this protein could conceivably be used as local anesthetics, anticon-
vulsants, or cardiac antiarrhythmics. An alternative to this approach (multiple targets–
one disease) is to select a specific pathological process (or disease) and then design
drugs to treat this process, using a diversity of different and varied druggable targets.
The medicinal chemistry of treating hypertension is a superb example of this latter
approach. Although hormones (mineralocorticoids, vasopressin, renin–angiotensin
system, natriuretic factors) are a logical starting point, considering their influence on
fluid and electrolyte homeostasis, they are not the only source of design strategies in
antihypertensive drug design.
Systemic arterial hypertension (“high blood pressure”) does not typically make the
afflicted individual feel unwell; however, after many years, it leads to vascular damage
and to the secondary complications thereof; hence, the designation of hypertension as
“the silent killer.” The ultimate aim of the pharmacological management of hyperten-
sion is to prevent these complications and thus to prolong not only life expectancy but
also quality of life.
Hypertension is a sustained elevation of the systemic arterial pressure. The arterial
pressure is determined by the cardiac output (amount of blood pumped) and the periph-
eral resistance in the arterial vessels (pressure = flow ×resistance); the peripheral resis-
tance is determined by the viscosity of the blood and by the caliber (and distensibility)
of the resistance vessels. The systolic pressure is the pressure being exerted against the
walls of the arteries during the time of peak cardiac contraction and blood ejection;
the diastolic pressure is the pressure being exerted against the arterial walls while the
heart vessels are refilling but not forcibly ejecting blood. Blood pressure is measured
as the ratio of the systolic pressure over the diastolic pressure. Although definitions
vary, hypertension reflects either a systolic pressure greater than 160 torr or a diastolic
378 MEDICINAL CHEMISTRY