MEDICINAL CHEMISTRY

for better drug in this series. Subsequently, phenformin was reported which is
comparatively more safe, nontoxic biguanide. It was soon followed by metformin,
another biguanide. These biguanides are usually represented by following general
formula.
R 1
R 2
N C
NH
H
N
NH
C
N
R 3
R 4
General formula for biguanides (199)
Biguanide derivatives lower the blood sugar in the absence of pancreatic islet cells; they
act in pancreatectomize animals and man but do not appreciably lower the blood sugar
level in normal subjects. Peripheral utilization of glucose is increased. Biguanides may
inhibit oxidative phosphorylation by inhibiting such oxidative enzymes as succinic
dehydrogenase. Respiratory enzyme inhibition results in cellular hypoxia; subsequently,
glucose uptake by the peripheral muscles increases and anaerobic glycolysis follows.
Owing to decrease in oxidation of adipose tissue, lipogenesis is also decreased. Because
of these differences in action, applications and usefulness these preparations differ from
those of the sulfonylurea compounds. They often lower the blood sugar content in
patients resistant to sulfonylurea compounds.
Phenformin (200) and Metformin (201) are similar in their in actions. The normal
therapeutic dose for both these biguanides ranges from 25 - 150 mg/day. They do not
stimulate insulin release but remain ineffective in the absence of insulin. Because of
lactic acidosis associated with the use of phenformin, it was withdrawn from the market.
CH 2 CH 2
NH NH
H
N C NH C NH2 Phenformin (Phenethyl Biguanide) (200)
H 3C
H 3C
NH
NH
N C NH C NH 2
Metformin (N, N-dimethylBiguanide) (201)
The possible mechanisms of action of these hypoglycemic biguanides include:
(a) Inhibition of intestinal transport and absorption of sugars.
(b) Potentiation of the action of insulin on glucose transfer processes into the cell.
(c) Inhibition of hepatic gluconeogenesis and
(d) Enhancement of glucose utilization processes and / or inhibition of oxidative
phosphorylation in the peripheral tissues.
Diguanidines
The two diguanidines i.e. synthaline A (202) and B (203) were reported to lower blood
glucose level in diabetic patients. High toxicity, failure to offer advantages over insulin
and a number of fatalities (renal and hepatic damages), associated with these drugs lead
to their clinical termination.