MEDICINAL CHEMISTRY

(i)HMG CoA-reductase Inhibitors: A new class of fungal derived compounds are
potent inhibitors of the enzyme β-Hydro-β-methyl-glutaryl-CoA reductase (HMG-CoA
reductase) (176) and includes compactin and mevinolin. This enzyme is the rate
determinig step in the endogenous synthesis of cholesterol. This enzymes are often
referred to collectively as statins' - a new class of lipid lowering agents. Compactin was
first isolated from the cultures of Penicillium species in 1976 by Endo while mevinolin
(or monacolin K) was isolated from the cultures of Aspergillus and Monascus species.
These drugs bring about specific, reversible and competitive blockage of HMG-CoA
reductase eading to decreased hepatic cholesterol synthesis. This induces an increased
rate of hepatic uptake and catabolism of circulating LDL. Thus the levels of total and
LDL-cholesterol are significantly reduced.
HO
CH 2COOH
C
CH 2C
O
CH 3
S CoA
HMG CoA (176)
Three statins, lovastatin (177), simvastatin (178) and pravastatin (179), have been
extensively studied. Simvastatin is a prodrug. The eliminating half-life of which is
relatively short,(I-3 hrs), but duration of enzyme inhibition is much longer.
HO
H 3C
COOH
OH
CH 3
O COC C 2H 5
R 2
R 1
Lovastatin (177): R 1= CH 3 ; R 2 = H
Simvastatin (178): R 1 = CH 3 ; R 2 = CH 3
Pravastatin (179): R 1 = OH ; R 2 = H
F
HO
N
Fluvastatin (180)
CO 2Na
The first drug of this class, mevastatin (1976) was isolated in Japan from Pencillium
species. But the first drug to be marketed from this class was lovastatin (I 987) which was
isolated from cultures of Aspergillus and Monscus. The success of lovastatin, therefore,
has prompted the development of additional synthetic HMGRIS resulting in the
marketing of pravastatin (epstatin) and simvastatin (synvinolin). Pravastatin was isolated
from Absidiacoerulea. The structures of these agents have been shown in the figures.
OH
H