MEDICINAL CHEMISTRY

3 rd Generation:
SO 2NHCONH
Glybormuride (214)
RCONHCH 2CH 2
Glypizide (215) where R =
SO 2NHCONH
N CH 3
Mechanism of Action: Sulfonyl ureas affect various plasma factors that influence the
insulin release.
(i) Sulfonyl ureas are found to be effective only in patients who retain functioning of islet
β-cells or in non-insulin-dependent diabetic patients. Hence the principal mechanism of
action is to stimulate the production and secretion of insulin by the β-cells of pancreas.
Glucose also stimulates insulin release but mechanism at molecular level differs from that
of sulfonyl ureas.
(ii)These drugs may lower down the output of glucose from the liver by insulin
independent mechanism.
(iii) Extrapancreatic effects: These effects could be linked to the hypoglycemic
activity of sulfonyl ureas. These effects include- inhibition of lipolysis, inhibition
of platelet aggregation, suppression of hepatic glucose output and enhancement of
glucagon secretion by the α-cells.
These extrapancreatic effects of the sulphonyl ureas have been observed, in
various organs including, liver fat and muscle.
SAR Studies
There must be reasonable bulk on the urea nitrogen; methyl and ethyl compounds are not
active. Usually, there is only one (normally substituent para) on the sulfonyl aromatic
ring. Many simple substituents are active, and the p-(P-arylcarboxamidoethyl) grouping
seen in second generation compounds is consistent with high potency. Among these
compounds, it is thought that the spatial relationship between the amide nitrogen of the
substituent and the sulfonamide nitrogen is important
SAR can be summarized into following points
(i) Certain substituents when placed at para position in benzene ring tend to
potentiate the activity, e.g. halogens, amino, acetyl, methyl, methylthio and
trifluoromethyl groups.
(ii) The size of terminal nitrogen along with its aliphatic substituent R, determines
lipophilic properties of the molecule. Optimum activity results when R consists
of 3 to 6 carbon atoms.
(iii) The nature of para substituents in benzene ring (-X-) appears to govern the
duration of action of the compound.
(iv) Aliphatic substituents (R) at the terminal nitrogen may also be replaced by an
alicyclic or heterocyclic ring.
(iv) Hypoglycemic activity can be related to the nature of sulfonyl grouping.
N