MEDICINAL CHEMISTRY

(ii)Fibric Acid Derivatives: A series of aryloxy-isobutyric acids was effective in
reducing plasma concentrations of triglyceride and cholesterol, Clofibrate (184), the first
compound of this class was clinically effective for the treatment of hypertriglyceridemia.
Several chemical analogs, congeners and homologs, collectively referred to as fibric
acids have been prepared with lesser toxicity. One of these, Gemfibrozil, has been
widely used.
Synthesis:
R 1 O C
CH 3
CH 3
Clorfibrate (184): R 1= Cl ; R 2 = C 2H 5
COOR 2
Fenofibrate (185):
O
R 1 = Cl C
R 2 = CH(CH 3) 2
CH3 Cl OH + CH3COCH3 + CH3Cl 1) NaOH
2) HCl
Cl O C COOH
(188)
H 3C
Cl O C COOCH 2CH 3
H 3C
Clorfibrate (184)
Structure-activity Relationships
Fibrates can be chemically classified as analogs of phenoxyisobutyric acid. The SAR for
this class of drugs is sparse; however, all compounds are analogs of the following general
structure (190).
(189)
CH 3
[Aromatic ring]-O-[Spacer group] C
O
C
OH
CH 3
(190)
The isobutyric acid group is essential for activity. Compounds containing an ester, such
as clofibrate and fenofibrate, are pro-drugs and require in vivo hydrolysis. Stibstitution at
the para position of the aromatic ring with a chloro group or chlorine containing
isopropyl ring produces compounds with significantly longer half-lives. While most
compounds contain a phenoxyisobutyric acid, the addition of an m-propyl spacer, as seen
in gemfibrozil, results in an active drug.
(iii) Bile-acid sequestrants: Bile acids are secreted by the liver into intestine where they
aid in the dissolution and absorption of lipids. Bile acids are the metabolic end-products
of cholesterol which are released into the intestine. Major fraction (about 98%) of bile
acids released into the gut is reabsorbed through the enterohepatic circulation and
suppresses the microsomal hydroxylase enzyme involved in the conversion of cholesterol
CH 3