MEDICINAL CHEMISTRY

Structure-activity Relationship
Mevastatin and lovastatin served as lead compounds in the development of additional
HMGRIS. The lactone and bicyclic rings as well as the ethylene bridge between them
responsible for the activity of HMGRIs. Additionally, it was found that the bicyclic ring
could be replaced with other lipophilic rings and that the size and shape of these other
ring systems were important to the overall activity of the compounds. Minor
modifications of the bicyclic ring and side chain ester of lovastatin produced simvastatin
and pravastatin . Pravastatin, a ring-opened dihydroxyacid with a 6'-hydroxyl group, is
much more hydrophilic than either lovastatin or simvastatin. Proposed advantages of this
enhanced hydrophilicity are minimal penetration into the lipophilic membranes of
peripheral cells, better selectivity for hepatic tissues, and a reduction in the incidence of
side effects seen with lovastatin and simvastatin.
The initial rationale centered on a desire to simplify the structures of mevastatin and
lovastatin. The 2, 4-dichlorophenyl analog (compound 181) shown below was one of the
first cornpounds to demonstrate that this type of substitution was possible. The
replacement of the bicyclic ring with various substituted, aromatic ring systems led to the
development of fluvastatin (180), atorvastatin (182), and cerivastatin.
Cl
HO
Cl
Compound (181)
O
H
O
F
HO
N
O
Atrovastatin (182)
H
CO 2Na
However, compound (181) was considerably less potent than mevastatin. Subsequent
research investigated a variety of aromatic substitutions and heterocyclic ring systems in
order to optimize HMGRI activity. The substituted pyrrole (compound 183) shown below
retained 30% of the activity of mevastatin and was a key intermediate in the substitutions
and the addition of spacer groups, have produced a number of active compounds.
F
HO
N
Compound (183)
H
O
O
OH
NH