Bioactive Agents from Natural Sources: Trends in Discovery and Application - Advances in Biochemical Engineering Biotechnology - page 108

2.3
Antihypercholesterolemic Drugs

For several years,lovastatin represented the commerically most successful drug
from nature. Named mevinolin, it was discovered as a metabolite from Asper-
gillus terreus cultures at the US company Merck by a target-directed screening
for inhibitors of3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase,
a key enzyme of cholesterol biosynthesis [32]. Cholesterol, which in humans
more than one-half of the total body cholesterol is derived from its de novo bio-
synthesis in the liver,is the major component ofatherosclerotic plaques built up
as fatty deposits on the inner walls of arteries, thus contributing to arte-
riosclerosis and coronary heart diseases [33].
A number of mevinolin like HMG-CoA reductase inhibitors comprising the
new type of a -lactone moiety linked to a decalin sidechain were isolated from

fungal strains such as Penicillium, Aspergillus, and Monascus spec. by various
groups and companies during the late 1970s and early 1980s [34-40].Mevinolin
and its analogs do not affect any other enzyme in the cholesterol biosynthesis
except HMG-CoA reductase (K i value of 6.4

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10 -10 ; rat liver enzyme [32]) thus
realizing a completely new therapeutic principle to treat hypercholesterolemia.
Mevinolin was the first HMG-CoA reductase inhibitor to be commercialized.It
was approved under the generic name oflovastatin (Mevacor) by Merck in 1987.
Later on, numerous lovastatin analogs developed by Merck and their com-
petitors followed. In 1994, simvastatin (Zocor), introduced by Merck in 1988,
took over the top position in the natural product based drugs sales list.Sankyo's
mevastatin, isolated and described prior to mevinolin, had to be modified to
reach the market under the generic name of pravastatin (Mevalotin) co-marke-
ted by Bristol-Myers Squibb in 1989.Pravastatin represents the first HMG-CoA
inhibiting drug with a opened ring dihydroxycarboxylic acid structure.
In contrast to pravastatin, lovastatin and its

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-lactone analogs have to be
metabolically activated to bind to the target site of the HMG-CoA reductase.
Cleavage of the

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-lactone moiety in the liver and in the cell culture system,
respectively,leads to the 3,5-dihydroxyvaleric acid form that mimics the struc-
ture of the proposed endogenous substrate consisting of an intermediate for-
med by mevalonic acid linked to coenzyme A. Thus, the dihydroxycarboxylic
acid form of lovastatin,and its analogs act as competitive inhibitors comprising
about 10,000- to 20,000-fold increased affinity to the target enzyme.Numerous
reports on the mode of action and structure/activity relationships have been
published [41-48]. The replacement of the decalin structure by certain sub-
stituted biaryl analogs retains potency,thus leading e.g.to the synthetic drugs
fluvastatin marketed by Sandoz [49],and Bay W 6228 developed at Bayer [50].
Presumably,manufacturing costs of both compounds are significantly reduced
relative to the fermentation based drugs lovastatin,simvastatin and pravastatin.
HMG-CoA reductase inhibiting drugs act within a highly complex bio-con-
trol system, and finally result in a plasma cholesterol decrease of up to 40%.
Sales rates of lovastatin and its analogs are still growing,and in 1994 their sales
reached more than US $3.6 billion.Although lovastatin and its analogs exhibit
only rare side-effects,a lot of people criticize the use of antihypercholesterole-

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