History of the Sulphonylureas

The history of sulphonylureas dates back to the beginning of the 20th century, when strenuous efforts were made to combat bacterial infections. Arsenic-based Salvarsan (Compound 606) was discovered by Ehrlich in 1910 [1] and was the first effective treatment for syphilis. Some years later, the German medical researcher Gerhard Domagk, working in the Bayer sector of I. G. Farbenindustrie, discovered in 1932 that azo-dyes (including some sulphonamide derivatives) were much more effective and less toxic as antimicrobial agents when given to animals. He was awarded the Nobel Price in 1939 for his work on Prontosil, a dark-red azo-dye that was introduced in 1935. Domagk and colleagues found that the azo-linkage in the prontosil molecule was rapidly cleaved in the body to release sulphonamide, which accounted for its antibacterial effect. During the following years many sulphonamides were synthesized and used to treat a number of infectious diseases.

In 1940, clinicians observed that some sulphonamides caused alkaline diuresis by inhibiting the carbonic anhydrase (CA) enzyme. After modification of the sulphonamide structure, azetazolamide was (in 1952) the first available CA inhibitor on the market. Azetazolamide was employed as a diuretic agent until the first thiazide diuretic, chlorothiazide, came along and proved much more effective in increasing sodium excretion. Further modifications led to the development of loop diuretics such as furosemide (1962) and bumetanide (1984). Thiazide modifications eventually resulted, more or less accidentally, in the discovery of hypotensive vasodilator drugs including diazoxide (1962).

The hypoglycaemic action of sulphonylsureas was also discovered by chance. In 1942, p-amino-sulfonamide-isopropyl-thiodiazole (IPTD)’s antibacterial effect on typhoid fever was studied by Janbon and colleagues in Montpellier [2], and they discovered that some of their subjects developed severe hypoglycaemia.

Loubatieres and his co-workers at the Department of Pharmacology at the University of Montpellier were working to establish a mode of action for the IPTD’s in 1946. Among other things, studies of the hypoglycaemia sulphonamides in dogs and rabbits showed that the degree of hypoglycaemia was dose dependent, and that there was an inverse relationship between the blood sugar and the blood sulphonamide level.

These active compounds were effective both by oral and parenteral administration, and they found that the sulphonamide group was a prerequisite for its hypoglycaemic action. Thus, Loubatieres’ conclusion was that these sulphonamide derivatives actions mimicked the actions of insulin[3],[4].

Loubatiere and his colleagues now wanted to test the efficacy of these drugs for the treatment of diabetes, but the timing was not good. In 1946, in the aftermath of World War II and its many associated political and social issues, the world’s attention was not focused on the improvement of diabetes treatment.

Loubatiers’ work was confirmed by Chen in 1946. He tested the cyclopropyl derivate and added the observation that compounds of thiodiazol lowered blood glucose levels in severely ill alloxan-diabetic animals[5]. This suggested that their effect was not confined to insulin release. In line with these findings, LaBarre and Reuse tested the action of IPTD on adrenalectomized animals, noting that observed that they were even more sensitive to its hypoglycaemic action. Furthermore, their blood glucose was still lowered when Alloxan was given to them in amounts that did not destroy their beta cells completely [6]. When Holt tested the same isopropyl compounds in normal animals a few years later he concluded that their effect was mainly on the pancreatic alpha cells, due to a suspected elimination of their glucagon secretion [7], [8].

From 1953-54, two new sulphonamide derivatives were developed: BZ-55, carbutamide and DH-860, tolbutamide. These were hypoglycaemic in normal animals and were the first to be tested for human use throughout the world. Bertram and Franke tested carbutamide in human subjects and found that it lowered blood glucose, eliminated glycosuria and replaced insulin, particularly in obese patients with adult onset of diabetes [9], [10]. Since their findings held together with Holt’s work, the Germans initially believed that the primary action of sulphonylureas was to lower glucagon secretion from the alpha cells.

In 1956, three conference reports presenting scientific data in this field were published from Canada, Germany and America [11][12][13]. When added to novel data from Loubatiere’s work on IPTD[14], these led to the revised interpretation that the sulphonamides work because they stimulate insulin release from the pancreatic beta cells. This would explain why the drugs were generally inactive in the absence of a sufficient beta-cell mass. Assays of insulin-like activity (ILAs) showed that sulphonylurea administration resulted in significant rises in blood ILA. Furthermore, chronic use of the drugs promoted beta cell growth in many cases.

Nonetheless, the precise action of the sulphonylureas was still causing confusion, given that the drugs seemed to potentiate the action of exogenous insulin in depancreatized animals, and to prevent the development of diabetes in patients given growth hormone chronically. Sulphonamides also exhibited additional powerful activities in vitro, inhibiting lipolysis and ketogenesis.

The first immunoassay for insulin did however demonstrate that sulphonamides are specific insulin secretagogues. Even so, there were some inconsistencies between the induced rises in insulin levels and the therapeutic effects of the sulphonylureas. Boshell together with Reaven and Dray suggested that several types of sulphonylureas improved glucose tolerance even though insulin levels remained low[15][16]. These effects were investigated and reviewed over the following 10 years while new molecular variants of the first-line drugs were developed and tested. Thus, some of the new sulphonylureas attained higher potency, longer duration of action and lower incidence of primary and secondary failures, but all in all the differences between them were only quantitative in nature[17][18].

In summary, data derived from both new and older generations of sulphonylureas suggested that the drugs stimulate insulin secretion, but after a longer treatment period (months or years), the drugs seemed able to control Figure 1: The history of sulphonylureas [21],[22], see text.
Figure 1: The history of sulphonylureas [21],[22], see text.
blood sugar even without sufficient stimulation of insulin secretion. It was therefore proposed that the drugs had two sites of action: on the beta cell membrane and on an unknown extrapancreatic site.

Although sulphonylureas were known to decrease blood glucose, the mode of action was not found until 1984, where the ATP sensitive potassium channel was discovered in pancreatic islets [19]. Finally in 1995, the specific binding site for sulphonylureas, subunit SUR-1 on the ATP sensitive potassium channel was revealed [20].

Figure 1: [21][22]

Brief pharmacology and mode of action

Look for details in

In brief, sulphonylureas lower blood glucose by stimulating insulin release from pancreatic beta cells. Sulphonylureas bind to the sulphonylurea receptor (SUR-1) and thereby inhibit the K+/ATP channel on beta cells in the pancreas. By inhibiting the receptor, the K+ flux decreases, causing the cell to depolarize and thereby opening of the voltage sensitive Ca2+ channels and allowing calcium inflow. The increased intracellular calcium causes vesicles containing insulin to fuse with the cell membrane and to secrete insulin and other vesicle content to the blood stream.

The most feared adverse effect is hypoglycaemia since SUs cause increased insulin secretion regardless of peripheral glucose levels. Although rare, hypoglycaemia remains a concern with sulphonylureas. Further, SUs generally cause 1-2 kg weight gain. Other adverse effects, rather rare, include nausea and vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, dermatologic reactions, alcohol-induces flush and hyponatraemia.

SUs in selected clinical trials

Tolbutamide and other first generation sulphonylureas revolutionized the treatment of diabetes by allowing glucose-lowering therapy to be extended to a much larger group of hyperglycaemic patients in whom diabetes had previously been considered not worthy of treatment. The utility of such intervention was tested in the notorious University Group Diabetes Program UGDP) trial, which showed no benefit of tolbutamide versus placebo. In contrast initial randomization to chlorpropamide in the UK Prospective Diabetes Study (UKPDS) was shown to be as effective as insulin in reducing microvascular complications of diabetes, while just failing to to show a statistically significant reduction in cardiovascular end-points. More recently, the ADVANCE study, using Gliclazide MR in the intensified treatment arm, once again demonstrated benefit in microvascular but not in macrovascular outcomes. Similar results have emerged from other trials using different treatment modalities in type 2 diabetes.

References

  1. ^ F. Bosch and L. Rosich, “The Contributions of Paul Ehrlich to Pharmacology: A Tribute on the Occasion of the Centenary of His Nobel Prize,” Pharmacology, vol. 82, no. 3, pp. 171–179, Oct. 2008.

  2. ^ Janbon M et al “Accidents hypoglycémiques graves par un sulfamidothiodiazol,” Montpellier Med., pp. 21–22, 1942.

  3. ^ A. Loubatieres, “Relations entre la structure moleculaire et l’activit hypoglycemiante des aminosulfonamides hypoglycemiantes,” Arch Int Physiol., pp. 174–177, 1944.

  4. ^ A. Loubatieres, “Étude Physiologique et Pharmacodynamique de Certains Dérivés Sulfamidés Hypoglycémiants,” Archives Internationales de Physiologie, 1946.

  5. ^ K. K. et. al Chen, “Hypoglycemic action of sulfanyl-amido-cyclopropylthiadiazole in rabbits and its reversal by alloxan,” Proc. Soc. Exp. Biol. Med., pp. 483–87, 1946.

  6. ^ J. LaBarre and J. Reuse, “A propos de l’action hypoglycemiante de certains derives sulfamides,” Arch. Neerl. Physiol., pp. 475–80, 1947.

  7. ^ C. Holt, B. Kroner, and J. Kuhnau, “Chemische Ausschaltung der A-Zellen der Langerhansschen Inseln.,” Naunyn Schmiedebergs Arch Exp Pathol Pharmakol., pp. 66–77, 1955

  8. ^ C. Holt et. al, “Wirkung von N1-sylfanyl-N2-n-butylcarmabid auf kohlenhydratsstoffwechsel und endokrines system,” Med. Wochenschr., Schweiz, pp. 1123–25, 1956.

  9. ^ P. Bertram, E. Bendtfeldt, and H. Otto, “Uber ein wirksames perorales antidiabeticum (BZ 55),” Dtsch. Med. Wochenschr., pp. 1455–60, 1956.

  10. ^ H. Franke and J. Fuchs, “Ein neues antidiabetisch prinzip,” Dtsch. Med. Wochenschr., pp. 1449–52, 1955.

  11. ^ “Conference on carbutamide.,” Can. Med. Assoc. J., pp. 957–1014, 1956.

  12. ^ “Report on Tolbutamide,” Dtsch. Med. Wochenschr., pp. 823–87, 1956.

  13. ^ R. Levine and G. G. Duncan, “Eds.: Symposium on Clinical and Experimental Effects of Sulfonylureas,” Metabolism, pp. 721–829, 1956.

  14. ^ A. Loubatieres and P. Bouyard, “Origine intrapancreatique de l’action hypoglycemiante et antidiabetique para-amino-benzene-sulfamido-isopropyl-thiodiazol.,” C.R. Acad. Sci., Paris, pp. 2044–48, 1956.

  15. ^ G. Reaven and J. Dray, “Effect of Chlorpropamide on Serum Glucose and Immunoreactive Insulin Concentrations in Patients with Maturity-onset Diabetes Mellitus,” Diabetes, vol. 16, no. 7, pp. 487–492, Jul. 1967.

  16. ^ B. Boshell and et al., “The effect of sulfonylurea agents on insulin secretion and insulin reserve.,” Excerpta Medica, vol. 1967, pp. 286–97.

  17. ^ W. Creutzfeldt, “Current views of the mode of action of hypoglycemic sulfonamides.,” Acta Diabetol Lat, vol. 1969, no. 6, pp. 201–15.

  18. ^ U. C. Dubach and A. Buckert, “Eds.: Recent Hypoglycemic Sulfonylureas,” Hans Huber Bern, vol. 1970.

  19. ^ D.L. Cook & N. Hales, Intracellular ATP directly blocks K+ channels in pancreatic B-cells, Nature 311, 271 - 273 (20 September 1984); doi:10.1038/311271a0

  20. ^ N. Inagaki et al., Reconstitution of IKATP: An Inward Rectifier Subunit Plus the Sulfonylurea Receptor, Science Vol 270, Issue 5239, pp. 1166-1170, 17 November 1995

  21. ^ Rang, Humphrey P. (2005). Drug Discovery and Development Technology in Transition (1st ed.) Churchill Livingstone Elsevier. ISBN-10: 0443064202. 360 pp. Rang, H. P. Chapter 1: The Development of the Pharmaceutical industry, page 10-12.

  22. ^ Brunton, Laurence L.; Lazo, John S.; Parker, Keith, eds. (2006). Goodman & Gilman’s The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. ISBN 0-07-142280-3. Oral hypoglycaemic agents, page 1634-1637.

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