This document discusses several classes of antihyperlipidemic agents including HMG-CoA reductase inhibitors, fibric acid derivatives, nicotinic acid, and ezetimibe. It outlines the key structural features and mechanisms of action for these drug classes. Specifically, it notes that HMG-CoA inhibitors work by mimicking enzyme intermediates, fibric acids require bioactivation, nicotinic acid lowers cholesterol, and ezetimibe inhibits intestinal cholesterol absorption. The document provides structural characteristics important for drug activity within each class.

1. ANTI
HYPERLIPIDEMIC
AGENTS
Dr. Naga Prashant Koppurauri,
M.Pharm, Ph.D, FAGE
Dept. of Pharmaceutical Chemistry

3. Hypothetical
model
of
lipoprotein
particle

4. Exogenous and endogenous pathways of lipoprotein metabolism.

8. Endogenous
and
exogenous
pathways
for
lipid
transport
and
metabolism.
FC, free unesterified cholesterol;
FFA, free fatty acids;
LCAT, lecithin-cholesterol acyltransferase;
LDLR, low-density lipoprotein recepto

11. Commercially
available
HMG-CoA
reductase
inhibitors

12. Mechanism
of
action
of
mevastatin
and
lovastatin.
Hydrolysis
of
these
prodrugs
produces
a
3,5-dihydroxy
acid
that
mimics
the
tetrahedral
intermediate
produced
by
HMG-
CoA
reductase.

13. Common for all HGMIs
1. The 3,5-dihydroxycarboxylate is essential for inhibitory activity. Compounds containing a lactone are
prodrugs requiring in vivo hydrolysis.
2. The absolute stereochemistry of the 3- and 5-hydroxyl groups must be the same as that found in
mevastatin and lovastatin.
3. Altering the two-carbon distance between C5 and the ring system diminishes or fails to improve activity.
4. A double bond between C6 and C7 can either increase or decrease activity. The ethyl group provides
optimal activity for
compounds containing ring A and some heterocyclic rings (e.g., pyrrole ring of atorvastatin). The ethenyl
group is optimal for compounds with other ring systems, including the indole, quinoline, and pyrimidine rings
seen in fluvastatin, pitavastatin, and rosuvastatin, respectively.

14. Ring A subclass
1. The decalin ring is essential for anchoring the compound to the enzyme active site. Replacement with a
cyclohexane ring resulted in a 10,000-fold decrease in activity.
2. Stereochemistry of the ester side chain is not important for activity; however, conversion of this ester to
an ether results in a decrease in activity.
3. Methyl substitution at the R2 position increases activity (i.e., simvastatin is more potent than lovastatin).
4. b-Hydroxyl group substitution at the R1 position enhances hydrophilicity and may provide some cellular
specificity.

15. Ring B subclass
1. Substituents W, X, Y, and Z can be either carbon or nitrogen; n is equal to either zero or one (i.e., five-
or six-member heterocyclic).
2. The para-fluorophenyl cannot be coplanar with the central aromatic ring. (Structural restraints to
cause coplanarity have resulted in a loss of activity).
3. R substitution with aryl groups, hydrocarbon chains, amides, or sulfonamides enhances lipophilicity
and inhibitory activity.

20. Fibric Acid

21. Bioactivation of clofibrate and chemical structures of other fibrates.

22. • The isobutyric acid group is essential for activity.
• Fenofibrate, which contains an ester, is a prodrug and requires in vivo
hydrolysis. Substitution at the para position of the aromatic ring with a
chloro group or a chlorine-containing cyclopropyl ring produces
compounds with significantly longer half-lives.
• Although most compounds contain a phenoxyisobutyric acid, the
addition of an n-propyl spacer, as seen in gemfibrozil, results in an
active drug.

25. NICOTINIC ACID

27. Ezetimibe lowers plasma cholesterol levels by inhibiting the absorption of
cholesterol at the brush border of the small intestine (17,23). Specifi cally,
ezetimibe has been proposed to bind to a specifi c transport protein located in the
wall of the small intestine, resulting in a reduction of cholesterol transport and
absorption

28. Synthesis of Clofibrate
Clofibrate
Clofibric acid