Page 220 - Medicinal Chemistry Self Assessment

2.22 Pravastatin and Fluvastatin 209

of activity with this analog. There are two aspects to consider. First, the addition of an extra carbon
atom may not be permitted due to the steric dimensions of the target enzyme, HMG CoA reductase.
The simple addition of a methyl group (or carbon atom) can significantly alter the interaction of a
drug molecule with its biological target. Although this may be the cause for the loss of activity, a
much bigger alteration in the steric dimension of fluvastatin has been introduced with this confor-
mational restriction. In evaluating the structure of fluvastatin, it is found that there is free rotation
about the bond that connects the indole ring to the para-fluoro aromatic ring. This allows flexibility
and the opportunity for these two rings to be oriented in a manner that allows optimal interactions
with HMG CoA reductase. In contrast, the conformational restriction introduced in the fluvastatin
analog creates a large, planar, tetracycline ring system with no flexibility. The ability of this analog to
interact with HMG CoA reductase would therefore be dependent on the availability of a complemen-
tary large, flat, hydrophobic area within the active site of the enzyme. Receptor binding studies have
shown that the para-fluoro aromatic ring of fluvastatin cannot be coplanar with the indole ring and
that conformational restriction, such as that shown in this question, abolishes therapeutic activity.

6. Pravastatin is primarily metabolite is inactive.
6. Pravastatin is primarily metabolized to its 3α epimer. This metabolite is completely inactive as an
HMG CoA reductase inhibitor. Identify the metabolic transformations required to produce this

metabolite and provide an explanation as to why this metabolite is inactive.

3D epimer

Answer

The epimer results from the oxidation of the 3β hydroxyl group by alcohol dehydrogenase followed
by reduction to the 3α epimer. The loss of activity results from the fact that the compound no longer
mimics HMG CoA or mevalonic acid. The epimeric hydroxyl group is oriented in the opposite direc-
tion and either fails to form a crucial hydrogen bond or sterically inhibits interaction with the active
site of HMG CoA reductase.