Sulfonylureas, Science and Serendipity
F. GILBERT McMAHON
The Upjohn Co., Kalmazoo, Mich.
Serendipity and structural modification of sul 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 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 made by been
serendipitous observations in man, rather than animal screening. that Human screening for a spec development programs trum of activities deserves consideration, so time-consuming 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.
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). 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 Table I. H N-^^-S0 -NH
sulfanilamide (1908) NH
1935: antibacterial activity
H N-^J>-N=N-HQ>-SO—NH prontosil (1932) N-N H N-1 — — — — — 1 1 —
5.7 5.7 36 33 — — 22 — — 1.3 4.7 —
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.
of the Various Sulfonylureas
GLASS III COMPOUNDS
1. 2. U - l 0,549 U - l 7,547
CLASS I V COMPOUNDS
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
1. 2. 3. 4.
U-14,184 U-14,262 U - l 3,398 U-i7,073