Molecular Modification in Drug Design

9 Sulfonylureas, Science and Serendipity F. GILBERT McMAHON

The Upjohn Co., Kalmazoo, Mich.

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on May 17, 2013 | http://pubs.acs.org Publication Date: January 1, 1964 | doi: 10.1021/ba-1964-0045.ch009

Serendipity and structural modification of sul fanilamides and sulfonylureas have advanced our ability to treat diabetes mellitus.

Attempts

to develop an agent clinically superior to tol butamide by chemical modification have been remarkably difficult in spite of animal human assay.

Over 6000 compounds

and have

been screened for hypoglycemic potency, and some structure-activity generalizations are pos sible.

Chemicals are made into therapeutic

products only in man. Animal screens are often based on a standard marketed product and may lead only to "me too" drugs. therapeutic

advances

have

Many major

been

made

by

serendipitous observations in man, rather than animal screening.

Human screening for a spec

trum of activities deserves consideration, so that

time-consuming

development

programs

are done on compounds known to possess hu man activity.

I η 1908 Gelmo discovered sulfanilamide while working with azo dyes. Other workers subsequently found that related sulfa compounds combined tena ciously with the proteins of wool and silk. This suggested the possibility that they might also react with bacterial protoplasm. A quarter of a century after Gelmo's synthesis, Domagk observed that mice with various bacterial infections could be protected by sulfonamides, an observation for which he was awarded a Nobel Prize in 1938. Of the 2,100,000 diagnosed diabetics in the United States today, 45% are on oral drugs, 33% are on insulin, and 22% are on diet alone. Approximately one million Americans take either tolbutamide or chlorpropamide every day as primary therapy for their diabetes mellitus. The sulfonylureas represent a very significant contribution to medical therapy. That guanidine bases de press blood sugar was first reported in 1918 by Watanabe (27). The real story of the antidiabetic sulfonamides began in 1942. In 1941 and 1942 sulfonamide derivatives were being studied extensively 102 In Molecular Modification in Drug Design; Schueler, F.; Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

9.

McMAHON

103

Sulfonylureas


for superior antibacterial properties. One of these, an isopropyl-thiadiazole derivative of sulfanilamide, was undergoing evaluation in patients with typhoid fever in France (27). When the clinician, Janbon, noted the symptoms of hypoglycemia occurring in some of his patients receiving this drug, he consulted Loubatières (18) ; and these two men initiated interest which has continued intensively to this time and which has produced effective antidiabetic therapeutic agents. Thus, the sequence of events indicates that molecular manipulation of the azo dyes produced sulfanilamide and prontosil and subsequent modification resulted in the sulfonylureas (Table I). Table I. H N-^^-S0 -NH 2

2

Sulfonylureas

2

sulfanilamide (1908) NH

1935: antibacterial activity 2

H N-^J>-N=N-HQ>-SO—NH 2

2

prontosil (1932) N-N H N-1 —

5.7 5.7 36 33 —

— — — — 1 1 —

— 22 — — 1.3 4.7 —

CLASS II COMPOUNDS

U-19,803 Metahexamide U - l 8,399 U-19,359 U-14,812 Cycloheptolamide U-14,827

3 3 4 4 2.2 4 2

In Molecular Modification in Drug Design; Schueler, F.; Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

9.

McMAHON

Sulfonylureas

107

of the Various Sulfonylureas GLASS III COMPOUNDS

R-/~\-SOo-NH-CO-NH—{(MS 1. 2.

U - l 0,549 U - l 7,547

CH CI— 3


CLASS I V COMPOUNDS

1.

U-14,184

2.

U-14,262

CH —

-N^-CH

3

3.

U - l 3,398

CI—

-N^-CH

3

4.

U-i7,073

CH

3

3

CH

3

CH

5.

U - l 6,444

CI—

6.

U-l 4,378

CH —

7.

U - l 6,002

CI—

8.

U-17,835

CH -

9.

U-12,504

CI-

~*0^

3

-

O

3

-

O

Duration of Effect for Sulfonylureas Normals Compound

Acute potency times tolbutamide

Duration

Half Life, Hours

CLASS III COMPOUNDS

U-10,549 U - l 7,547

2 3 CLASS I V COMPOUNDS

U-14,184 U-14,262 U - l 3,398 U-17,073 U - l 6,444 U - l 4,378 U - l 6,002 U-17,835 U-12,504

5 7 5 7+ 5 5 10 7 2-4

1 1 — 1 — 1 >1 1 >1

9.7 8.1 6.4 6.7 7.2 16-18


MOLECULAR MODIFICATION IN DRUG DESIGN


108

Table V gives the results of clinical experience with nine different sulfonylureas which have been given chronically to diabetic patients. The clinical data shown for U-14,812 (acetohexamide) are taken from the literature (3).

Discussion Correlation of Structure, Potency, and Duration. From the "acute potency" data shown, it will be noted that in Class IV sulfonylureas—i.e., in the semicarbazide derivaties—potency was far greater than the other three classes. In this group of compounds, the presence of an amino or chloro group in the



9.

McMAHON

Table V.

Sulfonylureas

109

Summary of Clinical Experience with Various Sulfonylureas Experience in Diabetics

Compound

Tolbutamide Carbutamide Chlorpropamide Metahexamide Cycloheptolamide U-12,504 U-17,835 U-14,184 U-14,812

No. pts. treated >1,000,000

1,000 > > 100,000 4,800 > 980 > 2,500 > 2,000 > 30 27

Pt. months

— — — —

>8000 >5000 >5000 50 68

Potency

1 3-4 4-7 10 3.7 5-10 5-10 7 1-4

Jaundice

Incidence of side effects, %

2?

1.5-3.2 5 or +

26/4800 0 3-8/2500 0 0 0

1-11 4.3

Molecular Modification in Drug Design

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