Hypocholesterolemic drugs

 

Atherosclerosis is generally viewed as a chronic, progressive disease
characterized by the continuous accumulation of atheromatous plaque
within the arterial wall. The past two decades have witnessed the
introduction of a variety of anti-atherosclerotic therapies. The statins
form a class of hypolipidemic drugs used to lower cholesterol by
inhibiting the enzyme HMG-CoA reductase, the rate-limiting enzyme
of the mevalonate pathway of cholesterol biosynthesis. Inhibition of
this enzyme in the liver stimulates low-density lipoprotein (LDL)
receptors, resulting in an increased clearance of LDL from the bloodstream
and a decrease in blood cholesterol levels. Through their
cholesterol-lowering effect, they reduce the risk of cardiovascular
disease, prevent stroke and reduce the development of peripheral
vascular disease. In addition, they are anti-thrombotic and antiinflammatory.

Nowdays there are a number of statins in clinical use. The entire
group of statins reached an annual market of nearly US$30 billion
before it became a generic pharmaceutical. The first member of the
group (compactin; mevastatin) was isolated as an antibiotic product
of Penicillium brevicompactum and later from Penicillium citrinum.
Although not of commercial importance, compactin’s derivatives
achieved overwhelming medical and commercial success. An ethylated
form, known as lovastatin (monacolin K; mevinolin), was isolated in
the 1970s in the broths of Monascus ruber and Aspergillus terreus.91
Lovastatin, the first commercially marketed statin, was approved
by the FDA in 1987. A semisynthetic derivative of lovastatin is
simvastatin, a major hypocholesterolemic drug, selling for US$7
billion per year before becoming generic. Another statin, pravastatin
(US$3.6 billion per year), is made through different biotransformation
processes from compactin by Streptomyces carbophilus92 and Actinomadura
sp.93 Other genera involved in the production of statins are
Doratomyces, Eupenicillium, Gymnoascus, Hypomyces, Paecilomyces,
Phoma, Trichoderma and Pleurotus.94 A synthetic compound, modeled
from the structure of the natural statins, is atorvastin, which has been
the leading drug of the entire pharmaceutical industry in terms of
market share (approximately US$14 billion per year) for many years.