DISCOVERY OF THE THIAZIDES: WHERE BIOLOGY AND CHEMISTRY MEET* KARL H. BEYER, JRA In 1971, the Albert Lasker Clinical Medical Research Award was presented to a good friend of ours, Dr. Edward D. Freis of the Veterans Administration. The citation was for having "demonstrated the effectiveness of the use of drugs in the treatment of hypertension; the life saving value of drugs in even moderate hypertension; and the dramatic reduction of deaths from stroke and congestive heart failure which can be realized when blood pressure is kept within normal limits." In his acceptance remarks [1 ], Dr. Freis wrote of"The Thiazides and Beyond" as follows: "In addition to lowering blood pressure, chlorothiazide greatly increased responsiveness to other hypotensive agents. Relatively small doses of the latter agents, when combined with chlorothiazide, resulted in a sustained reduction of blood pressure in the majority of patients. For the first time it was possible to control the blood pressure in the majority of patients with little discomfort or inconvenience." To Drs. Baer, Novello, Sprague, and myself, the usefulness of chlorothiazide and the stimulus it gave to later research in cardiovascular therapy have been a source of satisfaction in many ways. The recognition of our joint effort expressed by this 1975 Albert Lasker Special Award is especially meaningful. It is a privilege to recount the circumstances that led to chlorothiazide, and we believe it is useful to do so as an example of a fruitful research process. In our view, as expressed in the title of this report, a development such as the thiazide diuretics can be traced not merely to individuals but to the effective partnership of chemistry and biology, brought together on a rational basis in ideal circumstances. Each of us brought to the research a special dimension that derived ?Based on a presentation made at the scientific symposium held November 14 at the New York Hospital-Cornell Medical Center in association with the 1975 Albert Lasker Awards. The author and three of his Merck Sharp 8c Dohme Research Laboratories colleagues—James M. Sprague, Ph.D., John E. Baer, Ph.D., and Frederick C. Novello, Ph.D.—received the Albert Lasker Special Award for their research in this field. tVisiting Professor, Department of Pharmacology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033. 410 I Karl H. Beyer, Jr. ¦ Discovery ofThiazides COOH SO2NH2 SULFANILAMIDE SO.NH SCNH NH. SO P-CARBOXYBENZENESUI.FONAMIDE DICHLORPHENAMIDE r CHLORODISULFAMOYLANILINE CHLOROTHIAZIDE HYDROCHLOROTHIAZIDE Fig. 1.—Key compounds toward the discovery of chlorothiazide from his training and perspective. The chemists of our team, Frederick C. Novello andJames M. Sprague, were members ofthe organic chemistry department of which Sprague was the director. Their group had extensive background and experience in the field of sulfonamide chemistry, from which derived the company's substantial contributions to the sulfa drugs. This chemical background served our needs well and eventually led to the thiazides. John E. Baer and I were the pharmacologists principally involved in the program in those days when I was head of pharmacological research. Baer received his degree in organic chemistry after having worked in Dr. James M. Shannon's laboratory in New York. I met Baer there while visiting that laboratory to learn renal clearance techniques. My own advanced degrees were in medical physiology and medicine. The antecedents of the discovery can be found in a renal research program set up in 1943. The first renal studies were on the excretion of some of the sulfa compounds, for crystalluria was a common problem. Soon we took up the renal clearance of penicillin-G with the intent of inhibiting its rapid elimination. This work led to the discovery of probenecid (benemid), which is an interesting story and a useful drug in its own right. Indeed, from this research came a way of thinking and working that was to be important to the thiazide discovery. This was expressed in a paper from our laboratory entitled "Factors Basic to the Development of Useful Inhibitors of Renal Transport Mechanisms," first presented in Perspectives in Biology and Medicine ¦ Spring 1977 \ 411 1953 at the International Physiological Congress in Montreal [2]. That paper said, in part: It is the purpose of this communication to illustrate...
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Jan 1, 2019
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Richard E Brown + 5