STRUCTURE-ACTIVITY RELATIONSHIPS OF BENZOTHIADIAZINE COMPOUNDS AS HYPERGLYCEMIC AGENTS

¹ The Research Foundation of the Washington Hospital Center, and The George Washington University School of Medicine, Division of Clinical Pharmacology, Washington, D.C.

The effects of structural changes in a series of benzothiadiazine compounds on their hyperglycemic activity has been determined in rats. Correlation with the reduction in urine output in vivo and insulin production both in vivo and in vitro has also been assessed. The results show that for maximum hyperglycemic activity, inhibition of insulin secretion and reduction in urine output, these compounds must pomess (1) halogen substitution in the 6 or 7 position, (2) SO₂ group in the 1 position, (3) a double bond in position 3-4 of the heterocyclic ring and (4) simple alkyl substitution in the 3 position. The hyperglycemic response to the compounds may be explained by several mechanisms. The more potent compounds demonstrate an inhibition of insulin secretion, while this cannot be shown with the less active compounds. The latter may produce hyperglycemia through an extrapancreatic mechanism. Attention is drawn to the contrast between the chemical structure required for diuretic benzothiadiazines and the compounds described here and the close structural simllarity of the hypotensive benzothiadiazines described previously to the compounds described in this paper.