Pharmaceuticals–Some Important Drugs - Fundamentals of Industrial Chemistry: Pharmaceuticals, Polymers, and Business - page 187

A newer type of cholesterol drugs is based upon the direct inhibition of the
uptake of free cholesterol from the small intestine. Perhaps the most promi-
nent in this class is ezetimibe (Zetia ® , Schering-Plough Corporation). Note
that there are three chiral centers and therefore 2 3 or 8 possible stereoiso-
mers. The stereoisomers exhibit different cholesterol absorption inhibition
and therefore a single stereoisomer, as depicted, is administered [18].

OH

OH

N

F

O

F

Ezetimibe

11.3 HYPERTENSION

Heart disease is the leading cause of death in the U.S., representing about
25% of all deaths [19]. On average, an American dies every 39 seconds from
cardiovascular disease [20]. One third of the United States population older
than 19 has hypertension [21]. Hypertension is a major risk factor for car-
diovascular disease. Monotherapy adequately controls hypertension in only
about 50% of patients and therefore many require a combination of at least
two drugs to control blood pressure [22]. Common classes of medications for
the treatment of hypertension are angiotensin II receptor antagonists, ACE
inhibitors, calcium channel blockers, -blockers, and diuretics.

The renin angiotensin system is one of the most powerful regulators of
blood pressure. Renin, an enzyme, is secreted by the kidney in response to
a reduction in blood flow, blood pressure or sodium concentration. Renin
then converts angiotensinogen to angiotensin I, a decapeptide. Angiotensin
I is cleaved by angiotensin-converting enzyme (ACE) to angiotensin II, an
octapeptide which in turn activates angiotensin II receptors. Inhibition of the
action of angiotensin II at the receptors prevents the increase in blood pres-
sure caused by this hormone - receptor interaction. Medications that control
blood pressure by inhibiting the action of angiotensin II at the receptors are
in a class termed angiotensin II receptor blockers (ARBs).
The first receptor antagonist was losartan potassium (Cozaar ® , Merck)
[23]. Losartan potassium is a prodrug and is converted in the liver to an
active metabolite [24]. The term “prodrug” is used for an inactive substance
which is metabolized in-vivo to an active form. In other words, it is a drug
precursor.

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